Hand, Foot And Mouth Disease Research Articles

Seasonal and Meteorological Drivers of Hand, Foot, and Mouth Disease Outbreaks Using Data-Driven Machine Learning Models

Hand, Foot, and Mouth Disease (HFMD) predominantly affects children under the age of five and remains a significant public health concern in the Asia-Pacific region. HFMD outbreaks are closely linked to seasonal changes and meteorological factors, particularly in tropical and subtropical areas. In Thailand, a total of 657,570 HFMD cases were reported between 2011 and 2022 (12 years). This study aimed to identify the high- and low-risk HFMD outbreak areas using machine learning models: Logistic Regression (LR), Support Vector Machine (SVM), Decision Tree (DT), Random Forests (RF), Gradient Boosting Machine (GBM), and Extreme Gradient Boosting (XGBoost). Our findings showed that the XGBoost model outperformed the other models in predicting unseen data and defining the best model. The best model can be used to detect high-risk outbreak areas and to explore the relationship between meteorological factors and HFMD outbreaks. The results highlighted the seasonal distribution of high-risk HFMD outbreak months across different provinces in Thailand, with average maximum temperature, average rainfall, and average vapor pressure identified as the most influential factors. Furthermore, the best model was used to analyze HFMD outbreaks during the COVID-19 pandemic, showing a notable reduction in high-risk outbreak months and areas, likely due to the control measures implemented during this period. Overall, our model shows great potential as a tool for warnings, providing useful insights to help public health officials reduce the impact of HFMD outbreaks.

Completely conserved VP2 residue K140 of KREMEN1-dependent enteroviruses is critical for virus-receptor interactions and viral infection.

Hand, foot, and mouth disease (HFMD) annually affects millions of children worldwide. HFMD is caused by various enteroviruses, such as coxsackieviruses CVA6, CVA16, CVA10, and enterovirus 71 (EV-A71). Licensed inactivated EV-A71 vaccines do not provide cross-protection against other enteroviruses. There are no drugs specifically for HFMD. KREMEN1 (KRM1) serves as the cellular receptor for many HFMD-related enteroviruses, including CVA2-CVA6, CVA10, and CVA12. However, the molecular basis for broad recognition of these enteroviruses by the KRM1 receptor remains elusive. Here, we report that VP2 residue K140 (K2140) is completely conserved among all KRM1-dependent enteroviruses and is essential for virus-receptor binding and viral infection by interacting with residue D90 of KRM1. Overall, our findings provide a deeper understanding of the molecular basis of KRM1-dependent enterovirus infection in vitro and in vivo and may contribute to the development of broad-spectrum anti-enterovirus vaccines and treatments.

The Emergence of Coxsackievirus A16 Subgenotype B1c: A Key Driver of the Hand, Foot, and Mouth Disease Epidemic in Guangdong, China

Background: In 2024, mainland China witnessed a significant upsurge in Hand, Foot, and Mouth Disease (HFMD) cases. Coxsackievirus A16 (CVA16) is one of the primary causative agents of HFMD. Long-term monitoring of theCVA16 infection rate and genotype changes is crucial for the prevention and control of HFMD. Methods: A total of 40,673 clinical specimens were collected from suspected HFMD cases in Guangdong province from 2018 to 2024, including rectal swabs (n = 27,954), throat swabs (n = 6791), stool (n = 5923), cerebrospinal fluid (n = 3), and herpes fluid (n = 2). A total of 24,410 samples were detected as EV-positive and further typed by RT-PCR. A total of 872 CVA16-positive samples were isolated and further sequenced to obtain the full-length VP1 sequence. Phylogenetic analysis was performed based on viral protein 1 gene (VP1). Results: In the first 25 weeks of 2024, reported cases of HFMD were 1.36 times higher than the mean rates of 2023. In 2024, CVA16 predominated at 75.42%, contrasting with the past etiological pattern in which the CVA6 was predominant with the detection rate ranging from 32.85 to 77.61% from 2019 to 2023. Phylogenetic analysis based on the VP1 gene revealed that the B1a and B1b subtypes co-circulated in Guangdong from 2018 to 2022. The B1c outbreak clade, detected in Guangdong in 2023, constituted 68.24% of the 148 strains of CVA16 collected in 2024, suggesting a subtype shift in the CVA16 virus. There were three specific amino acid variations (P3S, I235V, and T240A) in the VP1 sequence of B1c. Conclusions: The new emergence of the CVA16 B1c outbreak clade in Guangdong during 2023–2024 highlights the necessity for the enhanced surveillance of the virus evolution epidemiological dynamic in this region. Furthermore, it is imperative to closely monitor the etiological pattern changes in Hand, Foot, and Mouth Disease (HFMD) in other regions as well. Such vigilance will be instrumental in guiding future vaccination strategies for HFMD.

The Immunogenicity of Coxsackievirus A6 (D3a Sub-Genotype) Virus-Like Particle and mRNA Vaccines.

In recent years, coxsackievirus A6 (CVA6) has surpassed enterovirus A71 to become the main pathogen causing severe Hand, Foot, and Mouth disease (HFMD) in China with a substantial disease burden. However, there is currently no commercial CVA6 vaccine. The D3a genotype of CVA6 is the predominant genotype in China. In this study, virus-like particles (VLPs) and mRNA vaccines based on the CVA6 sub-genotype D3a were successfully developed. The immunogenicity and protective effects of the VLP of CVA6 combined with Al(OH)3 and CpG adjuvant indicated that VLP-induced neutralizing antibodies against three CVA6 sub-genotype (D2, D3a, and D3b) strains in Institute of Cancer Research (ICR) mice, and the combination of the two adjuvants enhanced cellular immunity. Passive immunization with serum from mice immunized with VLPs protected suckling mice against CVA6 lethal challenge in both antiserum transfer and maternal immunization experiments. The immunogenicity and protective effects of the mRNA vaccine of CVA6 indicate that it induces robust T-cell immunity. T-cell immunity was found to cross-protect against coxsackievirus A10 infection in mice. This is the first trial of a CVA6 mRNA vaccine worldwide and the first comparison of the immunogenicity and protective effects of VLP and mRNA vaccines based on D3a CVA6. The study provides a theoretical basis for the development of enteroviruses vaccines and the formulation of immunization strategies.

In Vitro Discovery of a Therapeutic Lead for HFMD From a Library Screen of Rocaglates/Aglains.

The lack of effective antiviral treatments for enteroviruses, including human enterovirus A71 (EV-A71), have resulted in an immense global healthcare burden associated with hand-foot-and-mouth disease (HFMD). Rocaglates and aglains belong to a family of compounds produced by Aglaia genus plants. Since the initial discovery of rocaglates in 1982, various rocaglates and aglains have been synthesized and extensively studied mainly as anticancer agents. Here, we report the discovery of a novel aglain derivative as a potential EV-A71 inhibitor. From an immunofluorescence-based phenotypic screen of a library of 296 rocaglate and aglain derivatives, we identified a lead aglain which effectively suppressed EV-A71 replication by 2.3 log fold at a non-cytotoxic concentration, with a host cell CC50 of 21.78 µM, an EV-A71 infection EC50 of 3.57 µM, and a selectivity index of 6.1. Further validation revealed inhibition of EV-A71 across multiple human cell types and a pan-enterovirus inhibitory spectrum against other enteroviruses. Subsequent mechanistic investigation revealed interference with EV-A71 intracellular post-entry events including viral RNA transcription and translation. Findings from this study have established a strong foundation for development of aglain scaffolds as much needed antiviral agents for HFMD, paving the way for future medicinal chemistry optimization and in vivo studies.

6-thioguanine inhibits EV71 replication by reducing BIRC3-mediated autophagy

BackgroundEnterovirus 71 (EV71) is one of the major causative agents of hand, foot, and mouth disease (HFMD), and can cause severe cerebral complications and even fatality in children younger than 5 years old. However, there is no specific medication for EV71 infection in clinical practice. Our previous studies had identified the 6-thioguanine (6-TG), an FDA-approved anticancer drug, as a potential antiviral agent, but its anti-EV71 activity is largely unknown, therefore, we aim to explore the antiviral effect of 6-TG on EV71.Results6-TG significantly suppressed EV71 mRNA level, VP1 protein expression, and viral progeny production in HT-29 cells. In EV71-infected HT-29 cells, the 50% cytotoxicity concentration of 6-TG (CC50) was > 2000 µM and the 50% inhibitory concentration of 6-TG against EV71 (IC50) was 0.9302 µM. Interestingly, the selectivity index (SI) value of 6-TG against EV71 was > 2150.1, which was higher than the SI value (> 66.7) of ribavirin. Mechanistically, 6-TG treatment reduced the expression of baculoviral IAP repeat containing 3 (BIRC3), and further inhibited EV71 replication by attenuating BIRC3-mediated the complete autophagy.Conclusions6-TG exerted a significant inhibitory effect on EV71 infection in vitro and prevented EV71-induced the complete autophagy by decreasing BIRC3 expression. Our work provided a basis for the further development of 6-TG as a therapy for EV71-associated HFMD.

Influencing factors of hand, foot, and mouth disease based on structural equation modeling in Hubei, China

Hand, foot and mouth disease (HFMD) is a major public health issue in Hubei Province; however, research on the direct and indirect effects of factors affecting HFMD is limited. This study employed structural equation modeling (SEM) and geographically weighted regression (GWR) to investigate the various impacts and spatial variations in the factors influencing the HFMD epidemic in Hubei Province from 2016 to 2018. The results indicated that (1) with respect to the direct effects, the number of primary school students had the greatest positive direct effect on the number of HFMD cases, with a coefficient of 0.542. Socioeconomic factors strongly influence HFMD cases more directly than natural factors. (2) Concerning indirect effects, the minimum temperature, combined with the per capita disposable income of urban residents, had the greatest positive indirect effect on HFMD cases, with a coefficient of 0.022. Both natural and social factors had more substantial direct impacts on the HFMD epidemic than indirect impacts. (3) Regarding total effects, the number of primary school students, through various natural and social factors, had a total effect coefficient of 0.503 on HFMD incidence. (4) The number of primary school students, per capita GDP, and the number of hospital beds per thousand people had the most significant spatial impacts on HFMD cases. In underdeveloped regions, the HFMD epidemic is more heavily influenced by economic factors.

Optimization of Enterovirus-like Particle Production and Purification Using Design of Experiments

Hand, foot, and mouth disease (HFMD) represents an emerging health concern whose main causative agents are Coxsackievirus A6 (CVA6) and enterovirus A71 (EV71). The lack of a CVA6 vaccine and the rise of new HFMD-causing strains due to the containment of established HFMD-causing viruses necessitates the search for alternative vaccine technologies, including virus-like particle (VLP) vaccine candidates. While studies have demonstrated that production of enterovirus-like particles in various organisms can be achieved by expression of the viral P1 structural proteins and the 3CD protease, optimization based on the interplay between the three most commonly altered infection parameters (multiplicity of infection (MOI), viable cell density at the time of infection (VCD), and the infection period) is often not investigated. To address this challenge, we have performed Design of Experiments (DoE) to optimize the production of CVA6 and EV71 VLPs. Our results indicate that CVA6 VLP production peaks at high MOI, high VCD, and long infection periods. Our subsequent downstream purification processes yielded 38 mg and 158 mg of purified CVA6 and EV71 VLPs from 1 L crude harvest, respectively. This translates into thousands of potential vaccine doses and highlights the economic potential of enterovirus-like particles for vaccine purposes.

ILC3 Function as a Double-Edged Sword in EV71 Infection

Enterovirus 71 (EV71) is a common pathogen responsible for hand, foot, and mouth disease (HFMD), leading to severe neurological complications and even death. However, the mechanisms underlying severe EV71-induced disease remain unclear, and no effective specific treatments are available. In this study, we successfully infected mice of different ages using a mouse-adapted EV71 strain, resulting in disease and mortality. We compared immune system responses between infected and uninfected mice of different ages to identify key pathogenic targets during EV71 infection. Our findings revealed that the level of Group 3 Innate Lymphoid Cells (ILC3s) in mice negatively correlated with the severity of disease induced by EV71 infection. We conducted anti-ILC3 cytokine injections and cytokine neutralizing antibody experiments on 14-day-old EV71-infected mice. The results showed that the cytokine IL-17 secreted by ILC3 cells had a mild protective effect, while IL-22 promoted inflammatory responses. Our research demonstrates that ILC3 cells play a dual role in EV71 infection. These findings not only clarify key immune factors in the progression of EV71-induced disease but also provide a promising approach for the early diagnosis and treatment of severe EV71 infections.

Vaccines in Dermatology—Present and Future: A Review

Dermatological vaccines have emerged as critical tools in preventing and managing a wide spectrum of skin conditions ranging from infectious diseases to malignancies. By synthesizing evidence from existing literature, this review aims to comprehensively evaluate the efficacy, safety, and immunogenicity of vaccines used in dermatology, including both approved vaccines and those currently being researched. Vaccines discussed in this paper include those targeting dermatoses and malignancies (e.g., acne vulgaris, atopic dermatitis, and melanoma); infectious diseases (e.g., human papillomavirus (HPV); varicella zoster virus (VZV); herpes zoster (HZ); warts; smallpox; mpox (monkeypox); hand, foot, and mouth disease (HFMD); candidiasis and Group B Streptococcus (GBS); and neglected tropical diseases (e.g., Buruli ulcer, leprosy, and leishmaniasis). Through this review, we aim to provide a detailed understanding of the role of vaccines in dermatology, identify knowledge gaps, and propose areas for future research.

Construction of a Vero cell line expression human KREMEN1 for the development of CVA6 vaccines

Coxsackievirus A6 (CVA6) has emerged as a major pathogen causing hand, foot and mouth disease (HFMD) outbreaks worldwide. The CVA6 epidemic poses a new challenge in HFMD control since there is currently no vaccine available against CVA6 infections. The Vero cell line has been widely used in vaccine production, particularly in the preparation of viral vaccines, including poliovirus vaccines and EV71 vaccines. Unfortunately, most CVA6 strains failed to propagate effectively on Vero cells. The expression level of virus-specific receptors on the cell membrane significantly influences viral infection. Here, a Vero cell line with stable over-expressing of KREMEN1 (KRM1), a crucial receptor for CVA6, was constructed using the lentivirus system. The cloned cell line, called Vero-KRM1_#11, could efficiently support most CVA6 infections. The propagation of CVA6-TW00141 strain on Vero-KRM1_#11 was equal to that on RD cells. After four passages, the virus batch was obtained with a titer of about 107 TCID50/mL. Moreover, the purified CVA6 particles produced from Vero-KRM1_#11 or RD cells both could induce high and comparable levels of IgG and neutralizing antibodies. Importantly, passive transfer of the antisera from CVA6-vaccined mice showed 100% preventive efficacy against CVA6 infection in mice. Therefore, KRM1-expressing cells have the potential to serve as a valuable tool for the development and production of CVA6 or polyvalent HFMD vaccines.

Assessing the Role of Vaccination in the Control of Hand, Foot, and Mouth Disease Transmission

The impact of vaccination on the dynamics of hand, foot, and mouth disease (HFMD) transmission is explored in this paper, considering a fractional-order derivative system of equations. This model provides vaccination strategies and characterizes local and global stability using Lyapunov functions. This work computes the basic reproduction number (R0) to represent the endemic and epidemic scenarios. Additionally, sensitivity analysis was performed to identify the most critical parameters responsible for the disease dissemination. Our results indicate that vaccination plays a crucial role in controlling HFMD, significantly reducing its prevalence. These findings align with existing research, supporting the importance of effective vaccination strategies and public health interventions against HFMD. The fractional-order model captures the memory effect in infectious disease dynamics, providing further insight into modeling HFMD transmission compared to a traditional integer-order model. The results would contribute to effective vaccination strategies and public health interventions against HFMD.

Analysis of the Seasonal Distribution Characteristics of Hand, Foot, and Mouth Disease in a Southern China

Hand, foot, and mouth disease (HFMD) is a common infectious disease affecting children, particularly prevalent in Asian countries. In a city in southern China, the annual number of HFMD cases exceeds 40,000, yet this data has not been thoroughly analyzed to date. The Chinese Center for Disease Control and Prevention collected data on HFMD cases in this southern city from 2014 to 2019, with cases recorded on a monthly basis. We aimed to analyze the seasonal distribution characteristics of HFMD in the city using two methods: the Concentration Method and the Seasonal Index Method. The study aims to fill the existing data gap and provide insights for developing effective prevention and control strategies. Over the six-year period from 2014 to 2019, a total of 187,887 cases of HFMD were reported in the province. The average annual incidence rate was 48.94 per 100,000 population. The concentration ratio (M) was calculated to be 0.335, with annual M values ranging from 0.151 to 0.554, indicating a significant degree of seasonality in the incidence of HFMD. The seasonal index (C) exceeded 100% from April to July, peaking in June at 228.418%, which suggests that the epidemic season for HFMD in this city is from April to July. Given the distinct seasonal characteristics of HFMD in the southern city, it is imperative that prevention and control measures are implemented in advance of the peak season. Concurrently, robust surveillance and early warning systems should be maintained to mitigate the spread of HFMD and prevent outbreaks.

Childhood hand, foot and mouth disease sequelae cohort study in Henan, China: cohort profile

PurposeThe childhood hand, foot and mouth disease (HFMD) sequelae cohort study (HNHFMDCS) is an ambispective cohort study of patients with HFMD based in Henan Province, China, consisting of patients treated...

Trends in general practitioner consultations for hand foot and mouth disease in England between 2017 and 2022.

Hand, foot and mouth disease (HFMD) is a contagious communicable disease, with a high incidence in children aged under 10years. It is a mainly self-limiting disease but can also cause serious neurological or cardiopulmonary complications in some cases, which can lead to death. Little is known about the burden of HMFD on primary care health care services in the UK. The aim of this work was to describe trends in general practitioner (GP) consultations for HFMD in England from January 2017 to December 2022 using a syndromic surveillance network of GPs. Daily GP consultations for HFMD in England were extracted from 1 January 2017 to 31 December 2022. Mean weekly consultation rates per 100,000 population and 95% confidence intervals (CI) were calculated. Consultation rates and rate ratios (RR) were calculated by age group and sex. During the study period, the mean weekly consultation rate for HFMD (per 100,000 registered GP patients) was 1.53 (range of 0.27 to 2.47). In England, children aged 1-4years old accounted for the largest affected population followed by children <1years old. We observed a seasonal pattern of HFMD incidence during the non-COVID years, with a seasonal peak of mean weekly rates between months of September and December. HFMD is typically diagnosed clinically rather than through laboratory sampling. Therefore, the ability to look at the daily HFMD consultation rates provides an excellent epidemiological overview on disease trends. The use of a novel GP-in-hours surveillance system allowed a unique epidemiological insight into the recent trends of general practitioner consultations for HFMD. We demonstrate a male predominance of cases, the impact of the non-pharmaceutical interventions during the COVID-19 pandemic, and a change in the week in which the peak number of cases happens post-pandemic.

Identification of climate-sensitive disease incidences in vietnam: A longitudinal retrospective analysis of infectious disease rates between 2014 and 2022.

There is a growing correlation between the rise in infectious diseases and climate change; however, little is known about the interactions and mixed effects of climate factors on infectious diseases. We conducted a retrospective longitudinal study spanning 108 consecutive months from 2014 to 2022 in Can Tho, Vietnam to identify common infectious diseases (excluding tuberculosis, HIV, and COVID-19) and their associations with climate change and determine which common diseases presented concurrently with the COVID-19 period using multivariate linear regression, receiver operating characteristic (ROC) curve analysis, Bayesian kernel machine regression (BKMR) and orthogonal partial least squares discriminant analysis. The five infectious diseases with the highest average incidence rates per 100,000 people were diarrhea; hand, foot, and mouth disease (HFMD); dengue fever; viral hepatitis; and influenza. Positive associations with humidity were observed for dengue fever and HFMD. Temperature was positively associated with malaria. Negative associations were found between humidity and both chickenpox and tetanus. Diarrhea (AUC=0.79; 95% CL=0.70-0.87) and dengue fever (AUC=0.74; 95% CL=0.62-0.83) emerged as the most influential diseases both before and during the COVID-19 period. In our BKMR analysis, we found a significant association between the combined influence of temperature and humidity and the occurrence of dengue fever and HFMD, especially when all climate factors were at or above their 60th percentile relative to their values at the 50th percentile. Temperature emerged as the primary driver associated with the occurrence of infectious diseases. These findings underscore the importance of implementing robust surveillance, prevention, and control measures by public health authorities in Can Tho. Initiatives like vaccination campaigns, vector control programs, public education on hygiene practices, and strengthening healthcare infrastructure are crucial for mitigating the spread of infectious diseases and safeguarding public health in the region.

Exosomes in Oral Diseases: Mechanisms and Therapeutic Applications.

Exosomes, small extracellular vesicles secreted by various cells, play crucial roles in the pathogenesis and treatment of oral diseases. Recent studies have highlighted their involvement in orthodontics, periodontitis, oral squamous cell carcinoma (OSCC), and hand, foot, and mouth disease (HFMD). Exosomes have a positive effect on the inflammatory environment of the oral cavity, remodeling and regeneration of oral tissues, and offer promising therapeutic options for bone and periodontal tissue restoration. In OSCC tumor-derived exosomes promote cancer progression through cell proliferation, migration, invasion, and angiogenesis, and serve as potential biomarkers for early diagnosis and prognosis. Additionally, engineered exosomes constructed specifically based on exosome properties hold great promise for targeted drug delivery and regenerative therapies such as bone regeneration in orthodontics and periodontal healing. With continued research, exosomes hold great potential for improving diagnosis and treatment in oral diseases, advancing personalized and regenerative therapies.

An individualistic homoeopathic approach in treatment of hand foot mouth disease (HFMD) in adult: A case study

An individualistic homoeopathic approach in treatment of hand foot mouth disease (HFMD) in adult: A case study

Arginine depletion-induced autophagy and metabolic dysregulation are involved in the disease severity of hand, foot, and mouth disease

ABSTRACT Amino acid metabolism provides significant insight into the development and prevention of many viral diseases. Therefore, the present study aimed to compare the amino acid profiles of hand, foot, and mouth disease (HFMD) patients with those of healthy individuals and to further reveal the molecular mechanisms of HFMD severity. Using UPLC-MS/MS, we determined the plasma amino acid expression profiles of pediatric patients with HFMD (mild, n = 42; severe, n = 43) and healthy controls (n = 25). Brain tissues from CVA6-infected mice were examined using untargeted metabolomics. Several amino acids were significantly different between the three groups. Pathway analysis revealed that arginine, proline, and tryptophan metabolism are implicated in the pathogenesis of HFMD. A similar arginine depletion was observed in the brain tissues of CVA6-infected mice. Importantly, L-arginine supplementation improved the survival rate of CVA6-infected mice, inhibited virus multiplication, and reduced pathological autophagy associated with mTOR-autophagy pathway in the brain. Collectively, arginine, as the hub amino acid metabolite of the mammalian target of rapamycin (mTOR) signaling pathway affecting autophagy, plays an important role in the pathogenesis of severe HFMD. L-arginine supplementation may serve as a potential therapeutic option for critical patients with HFMD.

Isothermal nucleic acid amplification for monitoring hand-foot-and-mouth disease: current status and future implications.

With the global prevalence of the hand-foot-and-mouth disease (HFMD) epidemic, the development of reliable point-of-care testing (POCT) is crucial for the timely identification and prevention of outbreaks. Isothermal nucleic acid amplification techniques (INAATs) have attracted much attention because of their high efficiency for rapid diagnosis. In this work, we systematically summarize the current status of INAATs for HFMD and discuss advantages and drawbacksof various INAATs for HFMD. The INAATs for HFMD detection mainly include loop-mediated isothermal amplification (LAMP), simultaneous amplification and testing (SAT), and recombinase polymerase amplification (RPA). Among them, LAMP has excelled in several diagnostic metrics and has made significant progress in the field of POCT. SAT has been effective in overcoming the problem of RNA degradation. RPA is suited for on-site testing due to its rapid amplification rate and low reaction temperature. In addition, this study explores the potential of INAATs in lateral flow strips (LFS) test and microfluidic devices for HFMD. LFS is typically used for qualitative analysis and supports multiple detection. Microfluidics can integrate necessary processes of sample pre-processing, amplification, and signal output, enabling high-throughput qualitative or quantitative detection and demonstrating the potential of monitoring HFMD. We hope the current work will provide insights into INAATs for monitoring HFMD and serve as a reference for the implementation of on-site EV detection for public health.