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Enterovirus 71 (EV71) is a significant causative agent of hand, foot and mouth disease (HFMD). However, the precise mechanism by which EV71 infection leads to alterations in the immune response remain elusive. To address this knowledge gap, we conducted a study where we introduced the Inner Mongolia EV71 C33λ strain into Vero cells, derived from African green monkey kidney cells. Subsequently, we performed RNA sequencing (RNA-Seq) to investigate the changes in the transcriptome of these infected Vero cells. Our primary objective was to establish a foundational understanding that could inform future research on EV71-associated immune factors. In our study, we identified a total of 942 differentially expressed genes (DEGs) in Vero cells infected with Enterovirus 71 (EV71), with 568 gene exhibiting increased expression and 374 gene showing decreased expression. To elucidate the functional implications of these DEGs, we conducted a comprehensive functional enrichment analysis using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. This analysis revealed three genes that were significantly upregulated, which we subsequently validated using reverse transcription polymerase chain reaction technology (RT-qPCR). The RT-qPCR results were in strong agreement with our RNA-Seq data, confirming the reliability of our findings. This study represents the pioneering RNA-Seq analysis that delves into the cellular response of Vero cells to EV71 infection. Our results not only provide a foundational understanding of the molecular changes induced by EV71 but also offer crucial insights into the mechanisms by which EV71 modulates the host immune system. These insights are pivotal for future research endeavors aimed at developing effective therapeutic strategies against EV71 and related pathogens, as well as for understanding the broader implications of viral infections on host immunity. [ABSTRACT FROM AUTHOR]

Coxsackievirus A6 (CVA6) has become increasingly clinically relevant as a cause of Hand, Foot and Mouth Disease (HFMD) globally since 2008. However, most laboratories do not routinely determine the enteroviral type of positive samples. The non-pharmaceutical measures introduced to curb transmission during the COVID-19 pandemic may also have perturbed CVA6 epidemiology. We thus aimed to determine the prevalence, clinical presentation and genetic relationship of CVA6 across three complete epidemic seasons: one pre-SARS-CoV-2 emergence and two post-SARS-CoV-2 emergence in our regional healthcare setting. Surplus diagnostic nucleic acid from diagnosed enteroviral positives diagnosed between September and December of 2018 and between May 2021 and April of 2023 was subject to VP1 gene sequencing to determine the CVA6 cases and interrogate their phylogenetic relationship. The confirmed CVA6 cases were also retrospectively clinically audited. CVA6 infections were identified in 33 and 69 individuals pre- and post-pandemic, respectively, with cases peaking in November of 2018 and 2022, but in October of 2021. HFMD was the primary diagnosis in 85.5% of the post-pandemic cases, but only 69.7% of the pre-pandemic cases, where respiratory and neurological symptoms (45.5% and 12.1%, respectively) were significantly elevated. A complete VP1 sequence was retrieved for 94% of the CVA6 cases, revealing that studied infections were genetically diverse and suggestive of multiple local and international transmission chains. CVA6 presented a significant clinical burden in our regional U.K. hospital setting both pre- and post-pandemic and was subject to dynamic clinical and genetic epidemiology. [ABSTRACT FROM AUTHOR]

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 (PM2.5) and ozone (O3) to HFMD incidence across Sichuan-Chongqing counties. We further uncovered heterogeneous impacts of PM2.5 and O3 from three nonstationary perspectives. Numerically, PM2.5 showed an inverse 'V'-shaped relationship with HFMD incidence, while O3 exhibited a complex pattern, with increased HFMD incidence at low PM2.5 and moderate O3 concentrations. Temporally, PM2.5's impact peaked in autumn and was weakest in spring, whereas O3's effect was strongest in summer. Spatially, hotspot mapping revealed high-risk clusters for PM2.5 impact across all seasons, with notable geographical variations, and for O3 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract The influence of meteorological factors on hand, foot, and mouth disease (HFMD) is not on the same scale, it’s rare for previous studies to measure and recognize the independent regression relationship between each variable in space and time scale. This study used a multiscale geographically and temporally weighted regression (MGTWR) model to explore the relationship between the incidence of HFMD and related meteorological factors in Shandong Province, China, during 2015–2019 and attempted to quantify the influence of meteorological factors on HFMD under different spatiotemporal effects. Meanwhile, we used the Global Moran’s I statistic and Local Moran’s I statistic to test the spatial autocorrelation of the incidence of HFMD. HFMD had spatial autocorrelation at the county level in Shandong Province. The MGTWR model outperformed the OLS and GTWR models in determining the relationship between meteorological factors and HFMD. The study highlights significant spatiotemporal non-stationarity in the relationship between meteorological factors and HFMD. Temperature was predominantly positively correlated with HFMD, especially in the peninsula region during spring and summer. Humidity exhibited a predominantly positive correlation, especially in the Shandong Peninsula. Precipitation also showed a positive correlation with HFMD, particularly in western regions and during the winter months. Wind speed had a predominantly negative correlation with HFMD in the central and southwestern regions. The results might help public health authorities set priorities for targeted prevention and control measures in different regions and weather conditions, and provide guidance for the government to rationally allocate public health resources.

Abstract Background Coxsackievirus (CV) A6 has emerged as an important causative agent in global outbreaks of hand, foot, and mouth disease (HFMD), which typically presents as a mild illness with a large generalized rash, herpes. However, some patients can develop encephalitis, pneumonia, myocarditis and liver injury. Our previous study took the view that CVA6 could replicate in mouse liver, leading to acute liver injury; however, the precise underlying mechanism remains elusive. Methods 10-day-old wild-type (WT, C57BL/6J) and NLRP3 knock-out (KO) mice were intraperitoneal (i.p.) inoculated with a lethal dose of the CVA6 strain. The muscle homogenate supernatant from normal mice was used to inoculate mock-infected mice. At 5 days post infection (dpi), the mouse liver was taken out for histopathological analyses and molecular biology experiments. Results Our in vivo experiments demonstrated that CVA6 caused severe liver injury in mice, as evidenced by pathological changes in liver slices, elevated liver injury markers (e.g., AST, ALT, LDH) and pro-inflammatory cytokines (e.g., IL-6, MCP-1, TNF-α, IL-1β). Further results revealed the activation of NLRP3 inflammasome characterized by the increase in the expression of NLRP3, Cleaved-Casp-1 (p20), mature IL-1β and IL-18. Importantly, upon CVA6 infection, NLRP3 KO mice exhibited attenuated pathological damage and reduced levels of pro-inflammatory cytokines production (e.g., TNF-α and IL-1β) compared with WT mice. Finally, increased levels of blood ALT, AST, LDH were strongly correlated with the severity of CVA6 patients. Conclusion Collectively, our findings suggest that the activation of NLRP3 inflammasome is involved in CVA6 infection-induced acute liver injury, providing novel insights into CVA6 infection associated adverse clinical outcomes.

Abstract Background Hand, foot and mouth disease (HFMD) is a common infectious disease caused by viral infection by a variety of enteroviruses, with coxsackievirus A 10 (CA10) having become more prevalent in recent years. Methods In this study, models of CA10 infection were established in 7‐day‐old Institute of Cancer Research (ICR) mice by intraperitoneal injection to analyze the pathogenicity of the virus. RNA sequencing analysis was used to screen the differentially expressed genes (DEGs) after CA10 infection. Coxsackievirus A 16 (CA16) and enterovirus 71 (EV71) infections were also compared with CA10. Results After CA10 virus infection, the mice showed paralysis of the hind limbs at 3 days post infection and weight loss at 5 days post infection. We observed viral replication in various tissues and severe inflammatory cell infiltration in skeletal muscle. The RNA‐sequencing analysis showed that the DEGs in blood, muscle, thymus and spleen showed heterogeneity after CA10 infection and the most up‐regulated DEGs in muscle were enriched in immune‐related pathways. Compared with CA16 and EV71 infection, CA10 may have an inhibitory effect on T helper (Th) cell differentiation and cell growth. Additionally, the common DEGs in the three viruses were most enriched in the immune system response, including the Toll‐like receptor pathway and the nucleotide‐binding and oligomerization domain (NOD)‐like pathway. Conclusions Our findings revealed a group of genes that coordinate in response to CA10 infection, which increases our understanding of the pathological mechanism of HFMD.

Abstract 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 (PM2.5) and ozone (O3) to HFMD incidence across Sichuan-Chongqing counties. We further uncovered heterogeneous impacts of PM2.5 and O3 from three nonstationary perspectives. Numerically, PM2.5 showed an inverse ‘V’-shaped relationship with HFMD incidence, while O3 exhibited a complex pattern, with increased HFMD incidence at low PM2.5 and moderate O3 concentrations. Temporally, PM2.5’s impact peaked in autumn and was weakest in spring, whereas O3’s effect was strongest in summer. Spatially, hotspot mapping revealed high-risk clusters for PM2.5 impact across all seasons, with notable geographical variations, and for O3 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.

Hand, foot, and mouth disease (HFMD) is a clinical syndrome characterized by a febrile illness, followed by an oral exanthema and a macular, maculopapular, or vesicular rash of the hands, also involving palms, feet, and buttocks caused by enteroviruses of the picornaviridae family. It is a benign self-limiting disease which spreads by fecal–oral, oral–oral, and respiratory droplet contact. This case series describes cases of HFMD, presenting with typical clinical features in the North Indian region where early diagnosis and management of the condition can be carried out to halt the disease progression and prevention for the betterment of children. We came across four cases of HFMD in the month of early September to October. Their parents were health care workers, and the patients had typical symptoms and signs, except in one case, which showed extensive vesicular eruptions and crusting. All children improved at domiciliary care. Active communication and close monitoring are what is required to manage HFMD without complications. These cases infer that counseling and monitoring are an integral part in the management of HFMD.

ABSTRACT: Hand, foot, and mouth disease (HFMD) is a clinical syndrome characterized by a febrile illness, followed by an oral exanthema and a macular, maculopapular, or vesicular rash of the hands, also involving palms, feet, and buttocks caused by enteroviruses of the picornaviridae family. It is a benign self-limiting disease which spreads by fecal–oral, oral–oral, and respiratory droplet contact. This case series describes cases of HFMD, presenting with typical clinical features in the North Indian region where early diagnosis and management of the condition can be carried out to halt the disease progression and prevention for the betterment of children. We came across four cases of HFMD in the month of early September to October. Their parents were health care workers, and the patients had typical symptoms and signs, except in one case, which showed extensive vesicular eruptions and crusting. All children improved at domiciliary care. Active communication and close monitoring are what is required to manage HFMD without complications. These cases infer that counseling and monitoring are an integral part in the management of HFMD. [ABSTRACT FROM AUTHOR]

Background: Vaccination is a highly effective strategy for the prevention of enterovirus A71 (EV-A71)—hand, foot, and mouth disease (HFMD). Three inactivated EV-A71 vaccines in China have demonstrated remarkable efficacy against EV-A71-HFMD during clinical trials, exhibiting vaccine effectiveness (VE) exceeding 90% and few adverse events (AEs). However, the effectiveness of vaccines in the real world and its impact on the epidemiological characteristics of HFMD after the use of EV-A71 inactivated vaccine are uncertain. Methods: The odd ratio (OR) and 95% confidence (CI) were used as the effect estimates of the meta-analysis in the test-negative design (TND), and the OR was used to calculate VE: VE = (1 − OR) × 100%. Results: According to the literature search strategy, a comprehensive search was conducted in PubMed, Web of Science (including Chinese Science Citation Database and MEDLINE), and Embase, and 18 records were ultimately included in this study. Subsequently, the overall VE and 95% CI of different vaccine doses were analyzed, with the one-dose vaccine at 66.9% (95% CI: 45.2–80.0%) and the two-dose vaccine at 84.2% (95% CI: 79.4–87.9%). Additionally, the most reported AEs were mild general reactions without any rare occurrences. Simultaneously, the widespread use of the EV-A71 vaccine would lead to a reduction in both the incidence of EV-A71-associated HFMD and severe cases caused by EV-A71. Conclusion: The administration of the two-dose EV-A71 vaccine is highly effective in preventing HFMD in the real world, and the widespread use of the EV-A71 vaccine leads to a reduction in the incidence of EV-A71-associated HFMD and that of severe cases caused by EV-A71. The findings suggest that administering the two-dose EV-A71 inactivated vaccine to children aged 6 months to 71 months can be effective in preventing EV-A71-associated HFMD, highlighting the need for developing a multivalent HFMD vaccine for preventing cases not caused by EV-A71. [ABSTRACT FROM AUTHOR]

From 2011 to 2012, Northern Vietnam suffered its first large-scale hand, foot, and mouth disease (HFMD) epidemic. Two sets of official guidelines were issued during the outbreak to handle the HFMD crisis. The city of Hai Phong was used as a model to analyze the impact of the released guidelines. A total of 9621 HFMD cases were reported in Hai Phong city from April 2011 to December 2012. Three distinct waves of HFMD occurred. Enterovirus A71 and Coxsackievirus A16 were successively associated with the epidemics. Two periods, before and after the guidelines' release, could be distinguished and characterized by different patient patterns. The time to admission and severity changed notably. Guideline publications help the health system refocus on the 0.5–3 years age group with the highest incidence of the disease. The three waves showed different special distribution, but the main routes of infection were rivers and local secondary roads, most likely through local trade and occupational movements of people. [ABSTRACT FROM AUTHOR]

Hand, foot, and mouth disease (HFMD) is widely spread in China Mainland, seriously threatening the health of infants and young children. We develop a meta‐population model that includes both local and ecdemic populations to study the impacts of fomites and immigration on the transmission of HFMD in Shanghai. The model includes both direct transmission between susceptible and infected individuals (asymptomatic or symptomatic) and indirect transmission via fomites. The forward bifurcation shows that if the basic reproduction number is less than unity, the epidemic will die out; otherwise, the epidemic will spread. The fitting results show that the basic reproduction numbers of the local population and the ecdemic population are 1.4696 and 1.7288, respectively. Sensitivity analysis of the basic reproduction number showed that there was a high correlation between the basic reproduction number and the transmission rate of asymptomatic infected individuals, as well as the parameters related to the fomites (such as indirect transmission rate and virus shedding rate). Hence, asymptomatic infected individuals and fomites have a significant impact on the new HFMD infection. The numerical simulations on the prevention and control strategy show that reducing the transmission rate between susceptible and asymptomatic infected individuals or reducing the fomites can delay the outbreak of the epidemic and weaken the severity of HFMD. Our findings can provide guidance for the eradication of HFMD epidemic in the presence of indirect transmission and other factors. [ABSTRACT FROM AUTHOR]

BackgroundRecent HFMD cases have surged in Saudi Arabia, highlighting a literature gap on healthcare professionals’ understanding and attitudes towards HFMD. This study evaluates and compares knowledge and attitudes among medical students and physicians at the University of Jeddah.MethodsAn analytical cross-sectional study design was employed to survey medical students and physicians at the University of Jeddah from 1 November 2023 to 1 January 2024. Participants were assessed using multiple-item scales to measure their knowledge (max score: 23) and attitudes (max score: 32) towards HFMD. Logistic regression analysis was utilized to explore the association between various independent factors and the outcomes of interest (knowledge and attitude levels).ResultsA total of 317 responses (260 medical students and 57 physicians) were analyzed. Among medical students, the analysis of knowledge scores revealed a mean score of 6.36, with a standard deviation (SD) of 5.68, a median score of 6, and an interquartile range (IQR) of 0-10. About 31.6% of the students demonstrated adequate knowledge of HFMD. Notably, students who had received education on HFMD showed significantly higher levels of knowledge compared to those who had not. For student attitudes towards HFMD, the mean score in the attitude group was 20.1, with a SD of 4.2, a median of 20, and an IQR of 16 to 23. Among physicians, the mean knowledge score for those with adequate knowledge was 14.3, with a SD of 4.3 and a median of 15, and an IQR of 12-18. Furthermore, 54.4% of the physicians showed good knowledge, with being single significantly associated with this higher level of knowledge. In terms of attitudes among physicians, the mean score for the positive attitude group was 19.8, with a SD of 5.92, and a median score of 20, with an IQR of 16 to 25.ConclusionThe study highlights a significant gap in knowledge and attitudes towards HFMD among healthcare professionals in Saudi Arabia.

This study was conducted to efficiently produce virus-like particles (VLPs) of enterovirus 71 (EV71), a causative virus of hand, foot, and mouth disease (HFMD). The expression level of the P1 precursor, a structural protein of EV71, was modified to increase VLP production, and the optimal expression level and duration of the 3CD protein for P1 cleavage were determined. The expression level and duration of 3CD were controlled by the p10 promoter, which was weakened by repeated burst sequence (BS) applications, as well as the OpIE2 promoter, which was weakened by the insertion of random untranslated region sequences of various lengths. The cleavage and production efficiency of the P1 precursor were compared based on the expression time and level of 3CD, revealing that the p10-BS5 promoter with four repeated BSs was the most effective. When P1 and 3CD were expressed using the hyperexpression vector and the p10-BS5 promoter, high levels of structural protein production and normal HFMD-VLP formation were observed, respectively. This study suggests that the production efficiency of HFMD-VLPs can be significantly enhanced by increasing the expression of the P1 precursor and controlling the amount and duration of 3CD expression. [ABSTRACT FROM AUTHOR]

Hand, foot, and mouth disease (HFMD) is a contagious viral infection predominantly affecting infants and young children, caused by multiple enteroviruses, including Enterovirus 71 (EV71), Coxsackievirus A16 (CA16), Coxsackievirus A10 (CA10), and Coxsackievirus A6 (CA6). The high pathogenicity of HFMD has garnered significant attention. Currently, there is no specific treatment or broad-spectrum preventive measure available for HFMD, and existing monovalent vaccines have limited impact on the overall incidence or prevalence of the disease. Consequently, with the emergence of new viral strains driven by vaccine pressure, there is an urgent need to develop strategies for the rapid response and control of new outbreaks. In this study, we demonstrated the broad protective effect of maternal antibodies against three types of HFMD by immunizing mother mice with a trivalent inactivated vaccine targeting EV71, CA16, and CA10, using a neonatal mouse challenge model. Based on the feasibility of maternal antibodies as a form of passive immunization to prevent HFMD, we prepared a multivalent antiviral milk by immunizing dairy cows with the trivalent inactivated vaccine to target multiple HFMD viruses. In the neonatal mouse challenge model, this immunized milk exhibited extensive passive protection against oral infections caused by the three HFMD viruses. Compared to vaccines, this strategy may offer a rapid and broadly applicable approach to providing passive immunity for the prevention of HFMD, particularly in response to the swift emergence and spread of new variants. [ABSTRACT FROM AUTHOR]

Introduction and objective: The ailment commonly referred to as Boston exanthem disease is also known as hand, foot and mouth disease (HFMD). It is an infectious viral ailment usually of mild nature, triggered by enteroviruses and the coxsackie virus. Typical symptoms of HFMD include elevated temperature, fatigue, reduced appetite, abdominal and throat discomfort, painful mouth sores, and skin lesions. The incubation period ranges from 3-6 days, with symptoms persisting for 7-10 days. Today, the established diagnostic criteria for HFMD rely mainly on clinical symptoms and patient history. Most HFMD patients receive outpatient care with supportive measures alone, while isolation is recommended to reduce disease transmission. Generally, HFMD is mild and does not result in permanent damage. Dehydration stands as the primary complication, while the most severe consequences are associated with the central nervous system (CNS). This review was aimed at exploring the recent literature on HFMD, focusing on its epidemiology, aetiological factors, and novel strategies for its prevention and management. Material and methods: The authors' main goal was to summarise current scientific reports on the researched topic based on databases such as PubMed, Google Scholar, and taking into account their own materials (photos). Conclusions: The prevalence of this illness is rising. It is crucial to highlight its highly contagious nature, making it capable of rapid and widespread transmission. Understanding Boston exanthem disease and encompassing both typical and atypical symptoms is essential for accurate diagnosis and effective treatment protocols. This article discusses the most recent literature concerning HFMD, with a special focus on epidemiology, its defining traits and causative factors, and emerging strategies for its prevention and management. [ABSTRACT FROM AUTHOR]

Aim: In 2022, there was a severe hand, foot and mouth disease (HFMD) outbreak in India. This study focuses on the identification and molecular characterization of the causative agent. Methods: 51 suspected HFMD patients were examined. Viral RNA from HFMD-positive patients' vesicular extracts were sequenced. Phylogenetic analysis was carried out for genotype and mutation identification in current outbreak strains. Results: Phylogenetic analysis revealed a novel Indian clade of CVA16 belonging to genotype B1c. Two consistent mutations, R41H in the VP3 protein and G492T in the conserved 5′-UTR region, were found only in novel clade strains. Conclusion: The present study highlights the possibility and significance of the aforementioned mutations in increasing the ability of CVA16 to spread among adults. Hand, foot and mouth disease (HFMD) outbreaks are usually caused by a virus called Coxsackievirus A16. This virus mainly affects children under 5 years old. Our study looks at the virus that caused an outbreak of HFMD in India in 2022. This virus was found to have unique mutations its genetic material compared with previously reported strains. These mutations may have made the virus more able to spread and affect an adult population. These mutations should be studied further to develop treatments for future HFMD outbreaks caused by this new strain of Coxsackievirus A16. Article highlights In contrast to previous studies, the current study has a higher number of hand, foot and mouth disease positive cases in the adult population. Identification of a novel Indian clade of CVA16 belonging to B1c genotype. Two consistent mutations, R41H in the VP3 protein and G492T in the conserved 5′-UTR region, were found only in the novel Indian clade strains and could potentially be involved in the increased transmissibility of the virus in the adult population. [ABSTRACT FROM AUTHOR]

Coxsackievirus A6 (CVA6) has become increasingly clinically relevant as a cause of Hand, Foot and Mouth Disease (HFMD) globally since 2008. However, most laboratories do not routinely determine the enteroviral type of positive samples. The non-pharmaceutical measures introduced to curb transmission during the COVID-19 pandemic may also have perturbed CVA6 epidemiology. We thus aimed to determine the prevalence, clinical presentation and genetic relationship of CVA6 across three complete epidemic seasons: one pre-SARS-CoV-2 emergence and two post-SARS-CoV-2 emergence in our regional healthcare setting. Surplus diagnostic nucleic acid from diagnosed enteroviral positives diagnosed between September and December of 2018 and between May 2021 and April of 2023 was subject to VP1 gene sequencing to determine the CVA6 cases and interrogate their phylogenetic relationship. The confirmed CVA6 cases were also retrospectively clinically audited. CVA6 infections were identified in 33 and 69 individuals pre- and post-pandemic, respectively, with cases peaking in November of 2018 and 2022, but in October of 2021. HFMD was the primary diagnosis in 85.5% of the post-pandemic cases, but only 69.7% of the pre-pandemic cases, where respiratory and neurological symptoms (45.5% and 12.1%, respectively) were significantly elevated. A complete VP1 sequence was retrieved for 94% of the CVA6 cases, revealing that studied infections were genetically diverse and suggestive of multiple local and international transmission chains. CVA6 presented a significant clinical burden in our regional U.K. hospital setting both pre- and post-pandemic and was subject to dynamic clinical and genetic epidemiology.

Hand, foot, and mouth disease (HFMD) caused by various enteroviruses is a major public health concern globally. Human enterovirus 71(EVA71), coxsackievirus A16 (CVA16), coxsackievirus A6 (CVA6), and coxsackievirus A10 (CVA10) are four major enteroviruses responsible for HFMD. Rapid, accurate, and specific point-of-care (POC) detection of the four enteroviruses is crucial for the prevention and control of HFMD. Here, we developed two multiplex high-fidelity DNA polymerase loop-mediated isothermal amplification (mHiFi-LAMP) assays for simultaneous detection of EVA71, CVA16, CVA6, and CVA10. The assays have good specificity and exhibit high sensitivity, with limits of detection (LOD) of 11.2, 49.6, 11.4, and 20.5 copies per 25 μL reaction for EVA71, CVA16, CVA6, and CVA10, respectively. The mHiFi-LAMP assays showed an excellent clinical performance (sensitivity 100.0%, specificity 83.3%, n = 47) when compared with four singleplex RT-qPCR assays (sensitivity 93.1%, specificity 100%). In particular, the HiFi-LAMP assays exhibited better performance (sensitivity 100.0%, specificity 100%) for CVA16 and CVA6 than the RT-qPCR assays (sensitivity 75.0–92.3%, specificity 100%). Furthermore, the mHiFi-LAMP assays detected all clinical samples positive for the four enteroviruses within 30 min, obviously shorter than about 1–1.5 h by the RT-qPCR assays. The new mHiFi-LAMP assays can be used as a robust point-of-care testing (POCT) tool to facilitate surveillance of HFMD at rural and remote communities and resource-limited settings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Coxsackievirus-A6 (CV-A6) is responsible for more severe dermatological manifestations compared to other enteroviruses such as CV-A10, CV-A16, and EV-A71, causing HFMD in children and adults. Between 2005 and 2007, the recombinant subclade D3/RF-A started to expand globally, and a CV-A6 pandemic started. The study aimed to conduct whole-genome sequencing (WGS) of an isolated CV-A6 strain from currently circulating HFMD cases from India in 2022. Gene-specific RT-PCR and sequencing were used to perform molecular characterization of the isolated virus. Confirmation of these isolates was also performed by transmission electron microscopy and WGS. Among eleven positive clinical enterovirus specimens, eight CV-A6 strains were successfully isolated in the RD cell line. Isolates confirmed the presence of the CV-A6 strain based on VP1 and VP2 gene-specific RT-PCR. Sequences of isolates were clustered and identified as the novel CV-A6 strain of the D3/Y sub-genotype in India. The studies revealed that the D3/Y sub-genotype is being introduced into Indian circulation. The predicted putative functional loops found in VP1 of CV-A6 showed that the nucleotide sequences of the amino acid were a remarkably conserved loop prediction compatible with neutralizing linear epitopes. Therefore, this strain represents a potential candidate for vaccine development and antiviral studies. [ABSTRACT FROM AUTHOR]

Aim: This study focuses on the nonlinear characteristics of two linearly stable equilibrium states within a theoretical hand, foot and mouth disease (HFMD) dynamics model. Methods: The conditional nonlinear optimal perturbation method, the Lyapunov method and the linear singular vector method are employed. Results: By utilizing the conditional nonlinear optimal perturbation method, it is determined that the two linearly stable equilibrium states (namely the free disease and disease HFMD states) also exhibit nonlinear stability. It is found that the stabilities of the free disease and disease HFMD equilibrium states differ in terms of returning to their original states. Conclusion: It is discovered that nonlinearity plays a crucial role in reinstating the original equilibrium states. In this paper, from the perspective of stability analysis of equilibrium states, it is revealed that the stabilities of the free-disease and disease hand, foot and mouth disease equilibrium states differ in terms of returning to their original states. Through an examination of the nonlinearity factor in transmission, it is discovered that nonlinearity plays a crucial role in reinstating the original equilibrium states when using conditional nonlinear optimal perturbation-type and linear singular vector-type initial perturbations. Our results imply that it is important to consider nonlinear physical processes if one wants to be more prepared to forecast disease outbreaks, persistence and even seasonal characteristics. [ABSTRACT FROM AUTHOR]

Background: Hand, foot, and mouth disease (HFMD) is a common childhood infectious disease caused by a variety of enteroviruses (EVs). To explore the epidemiological characteristics and etiology of HFMD in Zhengzhou, China, we conducted a systematic analysis of HFMD surveillance data from Zhengzhou Center for Disease Control and Prevention from January 2009 to December 2021 (https://wjw.zhengzhou.gov.cn/). Methods: Surveillance data were collected from Zhengzhou Center for Disease Control and Prevention from January 2009 to December 2021 (https://wjw.zhengzhou.gov.cn/). Cases were analyzed according to the time of onset, type of diagnosis, characteristics, viral serotype, and epidemiological trends. Results: We found that the primary causative agent responsible for the HFMD outbreaks in Zhengzhou was Enterovirus A71 (EVA-71) (48.56%) before 2014. After 2015, other EVs gradually became the dominant strains (57.68%). The data revealed that the HFMD epidemics in Zhengzhou displayed marked seasonality, with major peaks occurring from April to June, followed by secondary peaks from October to November, except in 2020. Both the severity and case-fatality ratio of HFMD decreased following the COVID-19 pandemic (severity ‰: 13.46 vs. 0.17; case-fatality ‰: 0.21 vs. 0, respectively). Most severe cases were observed in patients aged 1 year and below, accounting for 45.81%. Conclusions: Overall, the incidence rate of HFMD decreased in Zhengzhou following the introduction of the EVA-71 vaccine in 2016. However, it is crucial to acknowledge that HFMD prevalence continues to exhibit a distinct seasonal pattern and periodicity, and the occurrence of other EV infections poses a new challenge for children's health.

Hand, foot, and mouth disease (HFMD) is one of the most common class C infectious diseases, posing a serious threat to public health worldwide. Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) have been regarded as the major pathogenic agents of HFMD; however, since an outbreak caused by coxsackievirus A6 (CV-A6) in France in 2008, CV-A6 has gradually become the predominant pathogen in many regions. CV-A6 infects not only children but also adults, and causes atypical clinical symptoms such as a more generalized rash, eczema herpeticum, high fever, and onychomadesis, which are different from the symptoms associated with EV-A71 and CV-A16. Importantly, the rate of genetic recombination of CV-A6 is high, which can lead to changes in virulence and the rapid evolution of other characteristics, thus posing a serious threat to public health. To date, no specific vaccines or therapeutics have been approved for CV-A6 prevention or treatment, hence it is essential to fully understand the relationship between recombination and evolution of this virus. Here, we systematically review the genetic recombination events of CV-A6 that have occurred worldwide and explore how these events have promoted virus evolution, thus providing important information regarding future HFMD surveillance and prevention.

From 2011 to 2012, Northern Vietnam suffered its first large-scale hand, foot, and mouth disease (HFMD) epidemic. Two sets of official guidelines were issued during the outbreak to handle the HFMD crisis. The city of Hai Phong was used as a model to analyze the impact of the released guidelines. A total of 9621 HFMD cases were reported in Hai Phong city from April 2011 to December 2012. Three distinct waves of HFMD occurred. Enterovirus A71 and Coxsackievirus A16 were successively associated with the epidemics. Two periods, before and after the guidelines’ release, could be distinguished and characterized by different patient patterns. The time to admission and severity changed notably. Guideline publications help the health system refocus on the 0.5–3 years age group with the highest incidence of the disease. The three waves showed different special distribution, but the main routes of infection were rivers and local secondary roads, most likely through local trade and occupational movements of people.

Background: Vaccination is a highly effective strategy for the prevention of enterovirus A71 (EV-A71)—hand, foot, and mouth disease (HFMD). Three inactivated EV-A71 vaccines in China have demonstrated remarkable efficacy against EV-A71-HFMD during clinical trials, exhibiting vaccine effectiveness (VE) exceeding 90% and few adverse events (AEs). However, the effectiveness of vaccines in the real world and its impact on the epidemiological characteristics of HFMD after the use of EV-A71 inactivated vaccine are uncertain. Methods: The odd ratio (OR) and 95% confidence (CI) were used as the effect estimates of the meta-analysis in the test-negative design (TND), and the OR was used to calculate VE: VE = (1 − OR) × 100%. Results: According to the literature search strategy, a comprehensive search was conducted in PubMed, Web of Science (including Chinese Science Citation Database and MEDLINE), and Embase, and 18 records were ultimately included in this study. Subsequently, the overall VE and 95% CI of different vaccine doses were analyzed, with the one-dose vaccine at 66.9% (95% CI: 45.2–80.0%) and the two-dose vaccine at 84.2% (95% CI: 79.4–87.9%). Additionally, the most reported AEs were mild general reactions without any rare occurrences. Simultaneously, the widespread use of the EV-A71 vaccine would lead to a reduction in both the incidence of EV-A71-associated HFMD and severe cases caused by EV-A71. Conclusion: The administration of the two-dose EV-A71 vaccine is highly effective in preventing HFMD in the real world, and the widespread use of the EV-A71 vaccine leads to a reduction in the incidence of EV-A71-associated HFMD and that of severe cases caused by EV-A71. The findings suggest that administering the two-dose EV-A71 inactivated vaccine to children aged 6 months to 71 months can be effective in preventing EV-A71-associated HFMD, highlighting the need for developing a multivalent HFMD vaccine for preventing cases not caused by EV-A71.

Abstract Objectives This study aims to investigate molecular epidemiology and clinical characteristics of enterovirus associated hand-foot-mouth disease (HFMD) in Chengdu, China, 2013–2022. Monitoring the molecular epidemiology and clinical features of HFMD for up to 10 years may provide some ideas for future protection and control measures. Methods We conducted a retrospective analysis of the medical records of all patients with laboratory-confirmed HFMD-related enterovirus infection at the West China Second University Hospital from January 2013 to December 2022. We described the characteristics in serotype, age, sex distribution and hospitalization of enterovirus infection cases using data analysis and graphic description. Results A total of 29,861 laboratory-confirmed cases of HFMD-related enterovirus infection were reported from 2013 to 2022. There was a significant reduction in the number and proportion of EV-A71 cases after 2016, from 1713 cases (13.60%) in 2013–2015 to 150 cases (1.83%) in 2017–2019. During the COVID-19 pandemic, EV-A71 cases even disappeared. The proportion of CV-A16 cases decreased from 13.96% in 2013–2015 to 10.84% in 2017–2019 and then to 4.54% in 2020–2022. Other (non-EV-A71 and non-CV-A16) serotypes accounted for 95.45% during 2020–2022, with CV-A6 accounting for 50.39% and CV-A10 accounting for 10.81%. Thus, CV-A6 and CV-A10 became the main prevalent serotypes. Furthermore, There was no significant difference in the enterovirus prevalence rate between males and females. The hospitalization rate of EV-A71 patients was higher that of other serotypes. In general, the proportion of HFMD hospitalizations caused by other pathogens except for EV-A71, CV-A16, CV-A10 and CV-A16 was second only to that caused by EV-A71. The proportion of children over 4 years old infected with enterovirus increased. Conclusion The incidence of HFMD associated with enterovirus infection has decreased significantly and CV-A6 has been the main pathogen of HFMD in Chengdu area in recent years. The potential for additional hospitalizations for other untested enterovirus serotypes suggested that attention should also be paid to the harms of infections with unknown enterovirus serotypes. Children with HFMD were older. The development of new diagnostic reagents and vaccines may play an important role in the prevention and control of enterovirus infection.

BackgroundThis study aimed to determine the intention and willingness-to-pay (WTP) of Chinese parents/guardians to vaccinate their children with the EV-71 vaccine. Knowledge levels about hand, foot, and mouth disease (HFMD) and the EV-71 vaccine were also investigated.MethodsA cross-sectional, self-administered online survey was conducted between November 2022 and March 2023. A stratified multi-stage random sampling method was used to recruit parents/guardians of children aged 0–5 years in southeastern China.ResultsA total of 3,626 complete responses were received. The mean knowledge score of HFMD was 9.99 (±4.23) out of a total of 14 points. The majority of the participants reported a somewhat willing intent (58.8%), followed by an extremely willing intent (28.9%). Participants who did not consider the EV-71 vaccine expensive (OR = 2.94, 95%CI 2.45–3.53) perceived that the EV-71 vaccine is effective (OR = 2.73, 95%CI 1.52–4.90), and a high knowledge level of HFMD (OR = 1.90, 95%CI 1.57–2.29) had the highest significant odds of having an extremely willing intent to vaccinate their children with the EV-71 vaccine. The median (interquartile range [IQR]) of WTP for the EV-71 vaccine was CNY¥200/USD$28 (IQR CNY¥100-400/USD$14-56). The highest marginal WTP for the vaccine was mainly influenced by the perceived high cost of the vaccine. Those participants who did not consider the EV-71 vaccine expensive had more than 10 times higher odds of vaccinating their children (OR = 10.86, 95%CI 8.49–13.88). Perceived susceptibility, perceived benefits, and perceived barriers were also significant influencing factors in the highest marginal WTP.ConclusionThe findings demonstrate the importance of improving health promotion and reducing the barriers to EV-71 vaccination. Therefore, it is important to improve health promotion and reduce the barriers to EV-71 vaccination.

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.

HFMD is an infectious disease that occurs in children under five, especially at school or daycare. This research aims to determine the effect of providing health education according to Islamic teachings on the level of parents' knowledge about HFMD in toddlers. The research design used Quasi-Experimental with Group Pretest and Post Test Design. The sample in this research was 22 respondents with a total sampling technique. The analysis used in this research was univariate analysis and paired t-test analysis. The results of the study used the paired t-test and found that there were significant differences in the pretest and posttest values of parents' knowledge about HFMD in children under five with a p-value of 0.000 (

BackgroundThe 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.MethodsThe 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.ResultsA 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.ConclusionThe 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.

BackgroundHand, 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.MethodsData 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.ResultsIn 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.ConclusionsFrom 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.

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 $ \mathcal {R}_0 $ 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 $ \mathcal {R}_0\le 1 $ 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 $ \mathcal {R}_0 $ 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. [ABSTRACT FROM AUTHOR]

An increasing number of studies have reported that atypical hand, foot, and mouth disease (HFMD) is becoming a new concern for children's health. At present, there is no official definition for atypical HFMD, but some studies have defined that it occurs at anatomic sites not listed in the definition of HFMD issued by the World Health Organization. Several pathogens have been reported to cause atypical HFMD, such as Coxsackievirus (CV)A6. As one of the most prevalent enteroviruses in the world, CVA6 seems to affect a wider range of children and causes more severe and prolonged illness than other enteroviruses. The early lesions of atypical HFMD are very similar to the clinical presentations of other diseases, such as eczema, which poses a challenge for clinicians aiming to identify and diagnose HFMD in a timely manner. Here, we report on six atypical HFMD patients caused by recombinant CVA6 variants, and the atypical manifestations include eczema coxsackium, large herpes, rice‐like red papules and herpes, purpuric rash, and onychomadesis, as well as and large red herpes on scalp, perianal, testicles, shoulders and neck, and other atypical eruption sites, hoping to draw the attention of other pediatricians. This study will provide scientific guidance for timely diagnosis of HFMD to prevent serious complications. [ABSTRACT FROM AUTHOR]

As a member of the enteroviruses, coxsackievirus A6 (CV-A6) has been a major cause of hand, foot, and mouth disease (HFMD) since 2008. It can infect both pediatric and adult populations, often leading to atypical HFMD. The host innate immune system plays a vital role in the development of enteroviral infections. However, the interplay between the host antiviral response and CV-A6 has not been well investigated. In the present study, we demonstrated that the 2C protein from CV-A6 (2CCV-A6) suppresses interferon beta (IFN-ß) production in HEK293T cells. Further results indicated that 2CCV-A6 interacts with both melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I) and induces the degradation of these RNA sensors through proteases in the lysosomal pathway. This function also applies to 2C proteins from enterovirus A71 (2CEV-A71) and coxsackievirus B3 (2CCV-B3) but not CV-A16 2C (2CCV-A16) for its incompetence in MDA5 and RIG-I recognition. Partial depletion and amino acid substitution analyses indicated that the F28A, V75A, and I96V mutations significantly compromised 2CCV-A6-induced MDA5/RIG-I depletion. Surprisingly, unlike V75A and I96V that interrupt the 2CCV-A6-MDA5/RIG-I interaction, 2CCV-A6 F28A remained competent in MDA5/RIG-I binding, suggesting that the interaction alone is not sufficient for 2C-mediated reduction. Additional tests indicated that CV-A6 viruses containing the 2C F28A mutation were less efficient in IFN-ß suppression, which is associated with compromised viral replication and release in infected rhabdomyosarcoma (RD) cells, suggesting that 2C-mediated immune regulation plays a vital role in enteroviral replication. Taken together, our data reveal a novel mechanism by which enteroviral 2C proteins antagonize the host innate antiviral immune response. [ABSTRACT FROM AUTHOR]

The fight against hand, foot, and mouth disease (HFMD) remains an arduous challenge without existing point‐of‐care (POC) diagnostic platforms for accurate diagnosis and prompt case quarantine. Hence, the purpose of this salivary biomarker discovery study is to set the fundamentals for the realization of POC diagnostics for HFMD. Whole salivary proteome profiling was performed on the saliva obtained from children with HFMD and healthy children, using a reductive dimethylation chemical labeling method coupled with high‐resolution mass spectrometry‐based quantitative proteomics technology. We identified 19 upregulated (fold change = 1.5–5.8) and 51 downregulated proteins (fold change = 0.1–0.6) in the saliva samples of HFMD patients in comparison to that of healthy volunteers. Four upregulated protein candidates were selected for dot blot‐based validation assay, based on novelty as biomarkers and exclusions in oral diseases and cancers. Salivary legumain was validated in the Singapore (n = 43 healthy, 28 HFMD cases) and Taiwan (n = 60 healthy, 47 HFMD cases) cohorts with an area under the receiver operating characteristic curve of 0.7583 and 0.8028, respectively. This study demonstrates the feasibility of a broad‐spectrum HFMD POC diagnostic test based on legumain, a virus‐specific host systemic signature, in saliva. [ABSTRACT FROM AUTHOR]

Introduction: Pathogen spectrum of Hand, foot and mouth disease (HFMD) has substantially changed in the past decade in China. Growing evidence has indicated that anti-COVID-19 nonpharmaceutical interventions (NPIs) can support control of various infectious diseases, including intestinal diseases. Methods: In this study, HFMD cases were enrolled from sentinel hospitals of Nanchang, Jiangxi province, and enteroviruses were genotyped using specific real time RT-PCR. We systematically characterized the epidemiology of HFMD based on the continuous molecular surveillance and estimated the impact of COVID-19 intervention on HFMD incidence using seasonal autoregressive integrated moving average (ARIMA) models. Results: A total of 10247 HFMD cases were included during 2010-2022, of which 6121 enterovirus (EV)-positive cases (59.7%) were identified by real-time RT-PCR. Over 80% cases were associated with EV-A71 and coxsackievirus A16 (CVA16) during 2010-2012, while the type distribution significantly changed as CVA6 emerged to be dominant, accounting for 22.6%-59.6% during 2013-2022. It was observed that the prevalence patterns of EV-A71 and CVA16 were similar and both of them peaked in the second quarter and then leveled off. However, CVA6 was generally prevalent around the fourth quarter, demonstrating a staggered prevalence during 2010-2019. During the COVID-19 epidemic, the seasonal HFMD epidemic peak was restrained, and the ARIMA analysis indicated that the COVID-19 intervention had mitigated EV transmission during the first COVID-19 outbreak in early 2020. In addition, bivariate Spearman's cross-correlation coefficients were estimated for the major types CVA6, CVA16 and EV-A71. Our analyses indicated the possible existence of correlations among CVA6, CVA16 and EV-A71 prevalence in the epidemiological level. Discussion: Taken together, the type distribution of HFMD has substantially changed over the last decade and CVA6 and CVA16 are currently the most predominant types co-circulating in Nanchang. The anti-COVID-19 NPIs significantly reduced the incidence of EV infections. [ABSTRACT FROM AUTHOR]

Enteroviruses are pathogens responsible for several diseases, being enterovirus A71 (EVA71) the second leading cause of hand, foot, and mouth disease (HFMD), especially in Asia–Pacific countries. HFMD is mostly common in infants and children, with mild symptoms. However, the disease can result in severe nervous system disorders in children as well as in immunosuppressed adults. The virus is highly contagious, and its transmission occurs via fecal–oral, oropharyngeal secretions, and fomites. The EVA71 burdens the healthy systems and economies around the world, however, up to date, there is no antiviral approved to treat infected individuals and the existent vaccines are not available or approved to be used worldwide. In this context, an extensive literature research was conducted to describe and summarize the recent advances in natural and/or synthetic compounds with antiviral activity against EVA71. The summarized data presented here might simply encourage the future studies in EVA71 antiviral development, by encouraging further research encompassing these compounds or even the application of the techniques and technologies to improve or produce new antiviral molecules. [ABSTRACT FROM AUTHOR]

Abstract Background Hand, foot and mouth disease (HFMD) caused by a variety of enteroviruses remains a major public health problem in China. Previous studies have found that social factors may contribute to the inconsistency of the relationship patterns between meteorological factors and HFMD, but the conclusions are inconsistent. The influence of social factors on the association between meteorology and HFMD is still less well understood. We aimed to analyze whether social factors affected the effect of meteorological factors on HFMD in Sichuan Province. Method We collected daily data on HFMD, meteorological factors and social factors in Sichuan Province from 2011 to 2017. First, we used a Bayesian spatiotemporal model combined with a distributed lag nonlinear model to evaluate the exposure-lag-response association between meteorological factors and HFMD. Second, by constructing the interaction of meteorological factors and social factors in the above model, the changes in the relative risk (RR) under different levels of social factors were evaluated. Results The cumulative exposure curves for average temperature, relative humidity, and HFMD were shaped like an inverted “V” and a “U” shape. As the average temperature increased, the RR increased and peaked at 19 °C (RR 1.020 [95% confidence interval CI 1.004–1.050]). The urbanization rate, per capita gross domestic product (GDP), population density, birth rate, number of beds in health care centers and number of kindergartens interacted with relative humidity. With the increase in social factors, the correlation curve between relative humidity and HFMD changed from an “S” shape to a “U” shape. Conclusions Relative humidity and average temperature increased the risk of HFMD within a certain range, and social factors enhanced the impact of high relative humidity. These results could provide insights into the combined role of environmental factors in HFMD and useful information for regional interventions.

Abstract Background This study adopted complete meteorological indicators, including eight items, to explore their impact on hand, foot, and mouth disease (HFMD) in Fuzhou, and predict the incidence of HFMD through the long short-term memory (LSTM) neural network algorithm of artificial intelligence. Method A distributed lag nonlinear model (DLNM) was used to analyse the influence of meteorological factors on HFMD in Fuzhou from 2010 to 2021. Then, the numbers of HFMD cases in 2019, 2020 and 2021 were predicted using the LSTM model through multifactor single-step and multistep rolling methods. The root mean square error (RMSE), mean absolute error (MAE), mean absolute percentage error (MAPE) and symmetric mean absolute percentage error (SMAPE) were used to evaluate the accuracy of the model predictions. Results Overall, the effect of daily precipitation on HFMD was not significant. Low (4 hPa) and high (≥ 21 hPa) daily air pressure difference (PRSD) and low ( 12 °C) daily air temperature difference (TEMD) were risk factors for HFMD. The RMSE, MAE, MAPE and SMAPE of using the weekly multifactor data to predict the cases of HFMD on the following day, from 2019 to 2021, were lower than those of using the daily multifactor data to predict the cases of HFMD on the following day. In particular, the RMSE, MAE, MAPE and SMAPE of using weekly multifactor data to predict the following week's daily average cases of HFMD were much lower, and similar results were also found in urban and rural areas, which indicating that this approach was more accurate. Conclusion This study’s LSTM models combined with meteorological factors (excluding PRE) can be used to accurately predict HFMD in Fuzhou, especially the method of predicting the daily average cases of HFMD in the following week using weekly multifactor data.

Hand, foot, and mouth disease (HFMD) is a contagious viral infection predominantly affecting infants and young children, caused by multiple enteroviruses, including Enterovirus 71 (EV71), Coxsackievirus A16 (CA16), Coxsackievirus A10 (CA10), and Coxsackievirus A6 (CA6). The high pathogenicity of HFMD has garnered significant attention. Currently, there is no specific treatment or broad-spectrum preventive measure available for HFMD, and existing monovalent vaccines have limited impact on the overall incidence or prevalence of the disease. Consequently, with the emergence of new viral strains driven by vaccine pressure, there is an urgent need to develop strategies for the rapid response and control of new outbreaks. In this study, we demonstrated the broad protective effect of maternal antibodies against three types of HFMD by immunizing mother mice with a trivalent inactivated vaccine targeting EV71, CA16, and CA10, using a neonatal mouse challenge model. Based on the feasibility of maternal antibodies as a form of passive immunization to prevent HFMD, we prepared a multivalent antiviral milk by immunizing dairy cows with the trivalent inactivated vaccine to target multiple HFMD viruses. In the neonatal mouse challenge model, this immunized milk exhibited extensive passive protection against oral infections caused by the three HFMD viruses. Compared to vaccines, this strategy may offer a rapid and broadly applicable approach to providing passive immunity for the prevention of HFMD, particularly in response to the swift emergence and spread of new variants.

This study was conducted to efficiently produce virus-like particles (VLPs) of enterovirus 71 (EV71), a causative virus of hand, foot, and mouth disease (HFMD). The expression level of the P1 precursor, a structural protein of EV71, was modified to increase VLP production, and the optimal expression level and duration of the 3CD protein for P1 cleavage were determined. The expression level and duration of 3CD were controlled by the p10 promoter, which was weakened by repeated burst sequence (BS) applications, as well as the OpIE2 promoter, which was weakened by the insertion of random untranslated region sequences of various lengths. The cleavage and production efficiency of the P1 precursor were compared based on the expression time and level of 3CD, revealing that the p10-BS5 promoter with four repeated BSs was the most effective. When P1 and 3CD were expressed using the hyperexpression vector and the p10-BS5 promoter, high levels of structural protein production and normal HFMD-VLP formation were observed, respectively. This study suggests that the production efficiency of HFMD-VLPs can be significantly enhanced by increasing the expression of the P1 precursor and controlling the amount and duration of 3CD expression.

Objectives: This study was performed to investigate the effect of non-pharmaceutical interventions on hand, foot, and mouth disease in Hubei Province China during the coronavirus disease 2019 pandemic. Methods: Data and samples were collected from the hand, foot, and mouth disease surveillance laboratory network in Hubei Province between 2018 and 2022. The samples were identified as Enterovirus A71, Coxsackievirus A6or Coxsackievirus A16 via real-time polymerase chain reaction. Representative Coxsackievirus A6 and Coxsackievirus A16 samples were sequenced and subjected to phylogenetic analyses. Results: A noticeable 3-fold reduction in the number of hand, foot, and mouth disease cases was observed from 2019 to 2020. The age and sex distributions of patients with hand, foot, and mouth disease were approximately the same from 2018 to 2022. The proportion of Coxsackievirus A6 accounted for 86 % in 2020 and 75 % in 2021 for hand, foot, and mouth disease compared with 48 % in 2018, 53 % in 2019, and 29 % in 2022. The proportions of Coxsackievirus A16 in 2020 and 2021 were 2 % and 17 %, respectively, showing a sharp decline in 2018 (37.8 %) and 2019 (35 %). In 2022, Coxsackievirus A16 was the dominant serotype (46 %). Only slight differences were found in the VP1 sequences across the different years. Conclusions: Our study confirmed that a series of non-pharmaceutical interventions during the coronavirus disease 2019 period reduced the transmission of enteroviruses and that long-term restrictions could significantly change the prevalence of enterovirus serotypes causing hand, foot, and mouth disease.

ABSTRACTWe 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 [Formula: see text] 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 [Formula: see text] 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 [Formula: see text] 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.

Objective: To investigate the effect of heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) on the replication of enterovirus 71 (EV-71) in SK-N-SH cells. Methods: The mRNA and protein expression of HNRNPA2B1 in SK-N-SH cells were detected by real-time quantitative PCR (qRT-PCR) and western blotting (WB), respectively. WB was used to detect HNRNPA2B1 protein expression in the nucleus and cytosol. The localization of HNRNPA2B1 protein in the nucleus and cytosol was detected by immunofluorescence (IF). The expression of HNRNPA2B1 was inhibited by small interfering RNA (si-HNRNPA2B1). Viral RNA, viral structural protein VP1, and viral titer were detected by qRT-PCR, WB, and viral dilution counting, respectively. Results: EV-71 infection significantly upregulates the expression of HNRNPA2B1 in SK-N-SH cells. EV-71 infection promotes HNRNPA2B1 nucleus-cytoplasm redistribution. Down-regulation of HNRNPA2B1 expression significantly inhibited EV-71 replication. Conclusion: HNRNPA2B1 protein redistributed from nucleus to cytoplasm and is highly expressed in the cytoplasm during EV-71 infection. Inhibition of HNRNPA2B1 levels effectively inhibits EV-71 replication in SK-N-SH cells.

Objectives: This study aims to investigate molecular epidemiology and clinical characteristics of enterovirus associated hand-foot-mouth disease (HFMD) in Chengdu, China, 2013–2022. Monitoring the molecular epidemiology and clinical features of HFMD for up to 10 years may provide some ideas for future protection and control measures. Methods: We conducted a retrospective analysis of the medical records of all patients with laboratory-confirmed HFMD-related enterovirus infection at the West China Second University Hospital from January 2013 to December 2022. We described the characteristics in serotype, age, sex distribution and hospitalization of enterovirus infection cases using data analysis and graphic description. Results: A total of 29,861 laboratory-confirmed cases of HFMD-related enterovirus infection were reported from 2013 to 2022. There was a significant reduction in the number and proportion of EV-A71 cases after 2016, from 1713 cases (13.60%) in 2013–2015 to 150 cases (1.83%) in 2017–2019. During the COVID-19 pandemic, EV-A71 cases even disappeared. The proportion of CV-A16 cases decreased from 13.96% in 2013–2015 to 10.84% in 2017–2019 and then to 4.54% in 2020–2022. Other (non-EV-A71 and non-CV-A16) serotypes accounted for 95.45% during 2020–2022, with CV-A6 accounting for 50.39% and CV-A10 accounting for 10.81%. Thus, CV-A6 and CV-A10 became the main prevalent serotypes. Furthermore, There was no significant difference in the enterovirus prevalence rate between males and females. The hospitalization rate of EV-A71 patients was higher that of other serotypes. In general, the proportion of HFMD hospitalizations caused by other pathogens except for EV-A71, CV-A16, CV-A10 and CV-A16 was second only to that caused by EV-A71. The proportion of children over 4 years old infected with enterovirus increased. Conclusion: The incidence of HFMD associated with enterovirus infection has decreased significantly and CV-A6 has been the main pathogen of HFMD in Chengdu area in recent years. The potential for additional hospitalizations for other untested enterovirus serotypes suggested that attention should also be paid to the harms of infections with unknown enterovirus serotypes. Children with HFMD were older. The development of new diagnostic reagents and vaccines may play an important role in the prevention and control of enterovirus infection. [ABSTRACT FROM AUTHOR]