RESUMEN

Hand, foot, and mouth disease (HFMD) is an acute infectious illness primarily caused by enteroviruses. The present study aimed to describe the epidemiological characteristics of hospitalized HFMD patients in a hospital in Henan Province (Zhengzhou, China), and to predict the future epidemiological parameters. In this study, we conducted a retrospective analysis of general demographic and clinical data on hospitalized children who were diagnosed with HFMD from 2014 to 2023. We used wavelet analysis to determine the periodicity of the disease. We also conducted an analysis of the impact of the COVID-19 epidemic on the detection ratio of severe illness. Additionally, we employed a Seasonal Difference Autoregressive Moving Average (SARIMA) model to forecast characteristics of future newly hospitalized HFMD children. A total of 19 487 HFMD cases were included in the dataset. Among these cases, 1515 (7.8%) were classified as severe. The peak incidence of HFMD typically fell between May and July, exhibiting pronounced seasonality. The emergence of COVID-19 pandemic changed the ratio of severe illness. In addition, the best-fitted seasonal ARIMA model was identified as (2,0,2)(1,0,1)12. The incidence of severe cases decreased significantly following the introduction of the vaccine to the market (χ2 = 109.9, p < 0.05). The number of hospitalized HFMD cases in Henan Province exhibited a seasonal and declining trend from 2014 to 2023. Non-pharmacological interventions implemented during the COVID-19 pandemic have led to a reduction in the incidence of severe illness.

Asunto(s)

COVID-19 , Enfermedad de Boca, Mano y Pie , Hospitalización , Estaciones del Año , Humanos , Enfermedad de Boca, Mano y Pie/epidemiología , Enfermedad de Boca, Mano y Pie/virología , China/epidemiología , Preescolar , Masculino , Femenino , Estudios Retrospectivos , Lactante , Estudios Longitudinales , Niño , COVID-19/epidemiología , Incidencia , Hospitalización/estadística & datos numéricos , Niño Hospitalizado/estadística & datos numéricos , Adolescente , Hospitales/estadística & datos numéricos , SARS-CoV-2 , Recién Nacido

RESUMEN

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

Asunto(s)

Enfermedad de Boca, Mano y Pie , Enfermedad de Boca, Mano y Pie/epidemiología , China/epidemiología , Humanos , Femenino , Masculino , Lactante , Preescolar , Niño , Adolescente , Recién Nacido , Aniversarios y Eventos Especiales , Análisis de Datos

RESUMEN

Introduction: Coxsackievirus A6 (CV-A6) has emerged as the predominant epidemic strain responsible for hand, foot and mouth disease (HFMD). CV-A6 infection can result in severe clinical manifestations, including encephalitis, meningitis, and potentially life-threatening central nervous system disorders. Our previous research findings demonstrated that neonatal mice infected with CV-A6 exhibited limb weakness, paralysis, and ultimately succumbed to death. However, the underlying mechanism of CV-A6-induced nervous system injury remains elusive. Numerous reports have highlighted the pivotal role of miRNAs in various viral infections. Methods: Separately established infection and control groups of mice were used to create miRNA profiles of the brain tissues before and after CV-A6 transfection, followed by experimental verification, prediction, and analysis of the results. Results: At 2 days post-infection (dpi), 4 dpi, and 2dpi vs 4dpi, we identified 175, 198 and 78 significantly differentially expressed miRNAs respectively using qRT-PCR for validation purposes. Subsequently, we predicted target genes of these differentially expressed miRNAs and determined their potential targets through GO (Gene Ontology) enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. Finally, we verified the miRNA-mRNA pairing via double luciferase experiments while confirming functional enrichment of target genes through Western Blotting analyses. Discussion: The results from this study suggest that transcriptional regulation, neuronal necrosis, pro-inflammatory cytokine release, and antiviral immunity are all implicated in the pathogenesis of central nervous system injury in mice infected with CV-A6. Brain injury resulting from CV-A6 infection may involve multiple pathways, including glial cell activation, neuronal necrosis, synaptic destruction, degenerative diseases of the nervous system. It can even encompass destruction of the blood-brain barrier, leading to central nervous system injury. The dysregulated miRNAs and signaling pathways discovered in this study provide valuable insights for further investigations into the pathogenesis of CV-A6.

Asunto(s)

Modelos Animales de Enfermedad , MicroARNs , Animales , MicroARNs/genética , MicroARNs/metabolismo , Ratones , Encéfalo/virología , Encéfalo/patología , Encéfalo/metabolismo , Infecciones por Coxsackievirus/virología , Infecciones por Coxsackievirus/genética , Lesiones Encefálicas/virología , Lesiones Encefálicas/genética , Perfilación de la Expresión Génica , Enterovirus Humano A/genética , Enterovirus Humano A/patogenicidad , Enterovirus/genética , Enterovirus/patogenicidad , Enfermedad de Boca, Mano y Pie/virología

RESUMEN

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

Asunto(s)

Enfermedad de Boca, Mano y Pie , Estaciones del Año , Enfermedad de Boca, Mano y Pie/epidemiología , Enfermedad de Boca, Mano y Pie/virología , Humanos , China/epidemiología , Masculino , Femenino , Preescolar , Lactante , Incidencia , Estudios Retrospectivos , Niño , Análisis Espacio-Temporal , Enterovirus/aislamiento & purificación , Prevalencia , Adolescente

RESUMEN

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

Asunto(s)

Enfermedad de Boca, Mano y Pie , Análisis Espacio-Temporal , Enfermedad de Boca, Mano y Pie/epidemiología , China/epidemiología , Humanos , Preescolar , Masculino , Estudios Retrospectivos , Femenino , Lactante , Niño , Incidencia , Adolescente , Factores de Riesgo , Recién Nacido

RESUMEN

Hand-foot-and-mouth disease (HFMD), which is typically seen in the younger pediatric population, is uncommon in older adolescent and young adult populations. We report on an atypical outbreak of HFMD among college students at a mid-size university in the mid-Atlantic U.S. The outbreak included 138 qualifying cases of HFMD among students at the institution between August and November 2018. All tested samples were positive for CVA6, a less common cause of HFMD. Signs and symptoms and campus mitigation strategies are described. This case report aims to highlight an atypical outbreak of HFMD for clinicians who care for older adolescent and college-aged patients in primary care and community settings, and may see cases and/or outbreaks of HFMD in these populations.

Asunto(s)

Brotes de Enfermedades , Enfermedad de Boca, Mano y Pie , Estudiantes , Humanos , Enfermedad de Boca, Mano y Pie/epidemiología , Masculino , Femenino , Estudiantes/estadística & datos numéricos , Universidades , Adulto Joven , Adolescente , Adulto

RESUMEN

Enterovirus 71 (EV-71) has strong neurotropism, and it is the main pathogen causing severe hand, foot, and mouth disease (HFMD). In clinical observations, significant differences were observed in the severity and prognosis of HFMD among children who were also infected with EV-71. Genetic differences among individuals could be one of the important causes of differences in susceptibility to EV-71-induced HFMD. As P-selectin glycoprotein ligand-1 (PSGL-1) is an important receptor of EV-71, the correlation between single-nucleotide polymorphisms (SNPs) in PSGL-1 and the susceptibility to severe HFMD following EV-71 infection is worth studying. Given the role of PSGL-1 in immunity, the correlations between PSGL-1 SNPs and the immune status after EV-71 infection are also worth studying. Meanwhile, PSGL-1 variable number of tandem repeats (VNTR) represents a research hotspot in cardiovascular and cerebrovascular diseases, but PSGL-1 VNTR polymorphism has not been investigated in HFMD caused by EV-71 infection. In this study, specific gene fragments were amplified by polymerase chain reaction, and PSGL-1 VNTR sequences were genotyped using an automatic nucleic acid analyzer. The correlations of PSGL-1 VNTR polymorphism with the susceptibility to EV-71-associated severe HFMD and the post-infection immune status were analyzed. The PSGL-1 VNTR A allele was identified as a susceptible SNP for severe HFMD. The risk of severe HFMD was higher for AA + AB genotype carriers than for BB genotype carriers. The counts of peripheral blood lymphocyte subsets were lower in AA + AB genotype carries than in BB genotype carries. In conclusion, PSGL-1 VNTR polymorphism is associated with the susceptibility to EV-71-induced severe HFMD and the immune status after infection. PSGL-1 VNTR might play a certain role in the pathogenesis of severe cases.

Asunto(s)

Enterovirus Humano A , Predisposición Genética a la Enfermedad , Enfermedad de Boca, Mano y Pie , Glicoproteínas de Membrana , Repeticiones de Minisatélite , Humanos , Enfermedad de Boca, Mano y Pie/genética , Enfermedad de Boca, Mano y Pie/inmunología , Enfermedad de Boca, Mano y Pie/virología , Glicoproteínas de Membrana/genética , Enterovirus Humano A/inmunología , Enterovirus Humano A/genética , Masculino , Femenino , Lactante , Repeticiones de Minisatélite/genética , Preescolar , Polimorfismo de Nucleótido Simple , Genotipo , Niño

RESUMEN

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

Asunto(s)

Evolución Molecular , Enfermedad de Boca, Mano y Pie , Enfermedad de Boca, Mano y Pie/epidemiología , Enfermedad de Boca, Mano y Pie/virología , China/epidemiología , Humanos , Epidemiología Molecular , Enterovirus Humano A/genética , Enterovirus Humano A/aislamiento & purificación , Enterovirus Humano A/clasificación , Filogenia , Enterovirus/genética , Enterovirus/clasificación , Enterovirus/aislamiento & purificación , Genómica , Masculino

RESUMEN

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

Asunto(s)

Enfermedad de Boca, Mano y Pie , Vigilancia de Guardia , Humanos , Enfermedad de Boca, Mano y Pie/epidemiología , Estudios Retrospectivos , República de Corea/epidemiología , Preescolar , Lactante , Niño , COVID-19/epidemiología , COVID-19/prevención & control , Recién Nacido

RESUMEN

BACKGROUND: There is evidence suggesting that Notch1 signaling pathway contributes to the development of hand, foot, and mouth disease (HFMD); however, the role of Notch1 gene polymorphisms in the severity of coxsackievirus A6 (CVA6)-related HFMD remains unclear. This study aimed to investigate the correlation between Notch1 gene polymorphisms and the severity of CVA6-related HFMD. METHODS: A total of 196 patients (Chinese Han population) diagnosed with CVA6-related HFMD through nucleic acid testing were included in this study. Among them, 97 patients were classified as severe cases, while 99 cases were categorized as mild. The mRNA levels of Notch1 in the peripheral blood leukocytes of HFMD patients were detected by quantitative real-time polymerase chain reaction (qRT-PCR), and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was utilized for genotyping of rs3124599, rs3124603, and rs3124591. RESULTS: The frequencies of rs3124599 alleles were G (39.0%) and A (61.0%), while the frequencies of rs3124599 genotypes were GG (12.2%), GA (53.6%), and AA (34.2%), respectively. In the recessive model, the frequency of rs3124599 AA genotypes significantly increased in severe patients, compared to mild patients (P < 0.05). Due to the low frequency of alleles for rs3124591 and rs3124603 in patients, as well as the absence of any difference in their distribution between the two groups (P > 0.05), no additional statistical analysis was performed. After adjusting for age and sex, patients with rs3124599 AA genotype had a significantly higher risk of severe HFMD in comparison to G allele carriers (GA/GG), with an odds ratio (95% confidence interval) of 2.010 (1.094, 3.691). Meanwhile, the mRNA levels of Notch1 were found to be significantly higher in severe patients compared to mild patients (P < 0.05), and a positive correlation was observed between Notch1 mRNA levels and the peripheral blood monocyte count (r = 0.42, P < 0.001). Additionally, there were significant differences observed in Notch1 mRNA levels and peripheral blood monocyte counts between patients with the AA genotype of rs3124599 and those with the GA genotype or G allele carriers (P < 0.05). CONCLUSION: In the Chinese Han population, there is a strong correlation between the Notch1 rs3124599 allele and the severity of CVA6-related HFMD. This correlation may be attributed to genetic polymorphism of rs3124599 regulating Notch1 transcription levels. These findings reveal the important role of Notch1 gene polymorphism in CVA6 infection, establishing a scientific foundation for the precise control of severe HFMD.

Asunto(s)

Alelos , Pueblo Asiatico , Enterovirus Humano A , Predisposición Genética a la Enfermedad , Enfermedad de Boca, Mano y Pie , Polimorfismo de Nucleótido Simple , Receptor Notch1 , Humanos , Masculino , Femenino , Enfermedad de Boca, Mano y Pie/genética , Enfermedad de Boca, Mano y Pie/virología , Receptor Notch1/genética , China/epidemiología , Preescolar , Lactante , Pueblo Asiatico/genética , Enterovirus Humano A/genética , Índice de Severidad de la Enfermedad , Frecuencia de los Genes , Genotipo , Niño , Pueblos del Este de Asia

RESUMEN

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

Asunto(s)

Enfermedad de Boca, Mano y Pie , Filogenia , Humanos , Beijing/epidemiología , Enfermedad de Boca, Mano y Pie/virología , Enfermedad de Boca, Mano y Pie/epidemiología , Masculino , Femenino , Preescolar , Lactante , Niño , Genotipo , Enterovirus/genética , Enterovirus/clasificación , Enterovirus/aislamiento & purificación , Proteínas de la Cápside/genética , Adolescente , Monitoreo Epidemiológico

RESUMEN

Hand, foot, and mouth disease (HFMD) is a common infectious disease caused by enteroviruses. Coxsackievirus A6 (CV-A6)-associated HFMD has recently emerged as a predominant disease worldwide. Here, we describe five HFMD cases caused by CV-A6 in Japan from 2019 to 2022. All clinical courses were not severe and were self-limited, and the skin exanthema with vesicles differed from that in classical HFMD. Phylogenetic analysis showed that the major epidemic strain cluster of CV-A6 was formed independently in 2011, and our latest CV-A6 strains in Japan were detected within this cluster. The five cases described in this report indicate the recent shift in the predominant and continuous disease manifestation of CV-A6-associated HFMD.

RESUMEN

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

Asunto(s)

Enterovirus , Enfermedad de Boca, Mano y Pie , Humanos , Enfermedad de Boca, Mano y Pie/epidemiología , Enfermedad de Boca, Mano y Pie/virología , Masculino , Femenino , China/epidemiología , Preescolar , Lactante , Enterovirus/genética , Enterovirus/aislamiento & purificación , Enterovirus/clasificación , Niño , Adolescente

RESUMEN

Enterovirus A71 (EV-A71) is a major pathogen causing hand, foot, and mouth disease (HFMD) in children worldwide. It can lead to severe gastrointestinal, pulmonary, and neurological complications. The innate immune system, which rapidly detects pathogens via pathogen-associated molecular patterns or pathogen-encoded effectors, serves as the first defensive line against EV-A71 infection. Concurrently, the virus has developed various sophisticated strategies to evade host antiviral responses and establish productive infection. Thus, the virus-host interactions and conflicts, as well as the ability to govern biological events at this first line of defense, contribute significantly to the pathogenesis and outcomes of EV-A71 infection. In this review, we update recent progress on host innate immune responses to EV-A71 infection. In addition, we discuss the underlying strategies employed by EV-A71 to escape host innate immune responses. A better understanding of the interplay between EV-A71 and host innate immunity may unravel potential antiviral targets, as well as strategies that can improve patient outcomes.

Asunto(s)

Enterovirus Humano A , Infecciones por Enterovirus , Interacciones Huésped-Patógeno , Evasión Inmune , Inmunidad Innata , Humanos , Evasión Inmune/inmunología , Enterovirus Humano A/inmunología , Enterovirus Humano A/patogenicidad , Interacciones Huésped-Patógeno/inmunología , Infecciones por Enterovirus/inmunología , Infecciones por Enterovirus/virología , Animales , Enfermedad de Boca, Mano y Pie/inmunología , Enfermedad de Boca, Mano y Pie/virología

RESUMEN

Background: The evidence on the effects of extreme meteorological conditions and high air pollution levels on incidence of hand, foot and mouth disease (HFMD) is limited. Moreover, results of the available studies are inconsistent. Further investigations are imperative to elucidate the specific issue. Methods: Data on the daily cases of HFMD, meteorological factors and air pollution were obtained from 2017 to 2022 in Jining City. We employed distributed lag nonlinear model (DLNM) incorporated with Poisson regression to explore the impacts of extreme meteorological conditions and air pollution on HFMD incidence. Results: We found that there were nonlinear relationships between temperature, wind speed, PM2.5, SO2, O3 and HFMD. The cumulative risk of extreme high temperature was higher at the 95th percentile (P95th) than at the 90th percentile(P90th), and the RR values for both reached their maximum at 10-day lag (P95th RR = 1.880 (1.261-2.804), P90th RR = 1.787 (1.244-2.569)), the hazardous effect of extreme low temperatures on HFMD is faster than that of extreme high temperatures. The cumulative effect of extreme low wind speeds reached its maximum at 14-day lag (P95th RR = 1.702 (1.389-2.085), P90th RR = 1.498(1.283-1.750)). The cumulative effect of PM2.5 concentration at the P90th was largest at 14-day lag (RR = 1.637 (1.069-2.506)), and the cumulative effect at the P95th was largest at 10-day lag (RR = 1.569 (1.021-2.411)). High SO2 concentration at the P95th at 14-day lag was associated with higher risk for HFMD (RR: 1.425 (1.001-2.030)). Conclusion: Our findings suggest that high temperature, low wind speed, and high concentrations of PM2.5 and SO2 are associated with an increased risk of HFMD. This study not only adds insights to the understanding of the impact of extreme meteorological conditions and high levels of air pollutants on HFMD incidence but also holds practical significance for the development and enhancement of an early warning system for HFMD.

Asunto(s)

Contaminantes Atmosféricos , Contaminación del Aire , Enfermedad de Boca, Mano y Pie , Enfermedad de Boca, Mano y Pie/epidemiología , China/epidemiología , Humanos , Incidencia , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Material Particulado/efectos adversos , Material Particulado/análisis , Preescolar , Femenino , Viento , Masculino , Lactante , Dióxido de Azufre/análisis , Dióxido de Azufre/efectos adversos , Conceptos Meteorológicos , Clima Extremo , Niño

RESUMEN

Background Hand, foot, and mouth disease (HFMD) is a viral illness commonly seen in children under five years of age, characterized by typical manifestations such as oral lesions and rashes on the hands and feet. Coxsackievirus A-16 (CV-A16) and Enterovirus A-71 (EV-A71) are the major etiological agents of this disease. Over the past two decades, there have been several outbreaks of HFMD all across India. As there is no chemoprophylaxis available for the disease, it becomes even more significant to conduct regular research and surveillance for HFMD. Aim and objective To observe the clinico-epidemiological profile along with constitutional symptoms in HFMD patients attending pediatric OPD. Methods This hospital-based prospective observational study was conducted in the Post Graduate Department of Pediatrics, Acharya Shri Chander College of Medical Sciences and Hospital (ASCOMS & H), Sidra, Jammu and Kashmir, India, over six months from April to September 2023. A total of 132 children with symptoms of HFMD visited the pediatric OPD. After using inclusive and exclusive criteria, we selected a sample size of 112 children with HFMD. The descriptive data were expressed in terms of percentages and proportions, and their graphical representation was done using MS Excel (Microsoft Corporation, Redmond, Washington, United States). Results Among the 112 HFMD patients examined, the highest peak was seen in August, followed by another one in September. Most of the cases were seen in the age group of zero to three years, and it was observed that there was a linear fall in the number of cases with the increase in age. Nearly 61% of cases were male, showing a slight male preponderance. Vesiculopapular rash on the hand and foot was the most common clinical characteristic, whereas painful deglutition was noted to be the most common constitutional symptom in HFMD patients. About 27% had a positive family history, and nail changes post-recovery were present in 1.79% of cases during their regular follow-ups. Conclusions This study reveals that HFMD cases surged in August and September, with a history of contact in one-fourth of cases. Disease is seen more commonly in children under three years of age, and the incidence of cases decreases with the increase in age. The illness is usually contagious and can spread quickly; therefore, more awareness programs should be done to educate parents and promote hygiene to prevent contact cases.

RESUMEN

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

Asunto(s)

Enfermedad de Boca, Mano y Pie , Filogenia , Enfermedad de Boca, Mano y Pie/epidemiología , Enfermedad de Boca, Mano y Pie/virología , Humanos , China/epidemiología , Masculino , Femenino , Preescolar , Lactante , Estudios Retrospectivos , Niño , Incidencia , Enterovirus/genética , Enterovirus/aislamiento & purificación , Enterovirus/clasificación , Serogrupo , Brotes de Enfermedades/estadística & datos numéricos , Adolescente

RESUMEN

Hand, foot, and mouth disease (HFMD) poses a significant public health threat primarily caused by four major enteroviruses: enterovirus 71 (EV71), coxsackieviruses A16, A10, and A6. Broadly protective immune responses are essential for complete protection against these major enteroviruses. In this study, we designed a new tetravalent immunogen for HFMD, validated it in silico, in vivo evaluated the immunogenicity of the DNA-based tetravalent vaccine in mice, and identified immunogenic B-cell and T-cell epitopes. A new tetravalent immunogen, VP1me, was designed based on the chimeric protein and epitope-based vaccine principles. It contains a complete EV71 VP1 protein and six reported neutralizing B-cell epitopes derived from the four major enteroviruses causing HFMD. In silico validation using multiple immunoinformatic tools indicated good attributes of the VP1me immunogen suitable for vaccine development. The VP1me-based DNA vaccine efficiently induced both humoral and cellular immune responses in BALB/cAJcl mice. A combination of in silico prediction and immunoassays enabled the identification of immunogenic linear B-cell and CD8 T-cell epitopes within the VP1me immunogen. Immunodominant linear B-cell epitopes were identified in six regions of VP1me, with one epitope located at the N-terminus of the VP1 protein (aa 9-23) regarded as a novel epitope. Interestingly, some B-cell epitopes could also induce the CD8 T-cell response, suggesting their dual functions in immune stimulation. These results lay the groundwork for further development of VP1me as a new vaccine candidate.

Asunto(s)

Anticuerpos Antivirales , Epítopos de Linfocito B , Enfermedad de Boca, Mano y Pie , Epítopos Inmunodominantes , Ratones Endogámicos BALB C , Vacunas de ADN , Vacunas Virales , Animales , Vacunas de ADN/inmunología , Epítopos de Linfocito B/inmunología , Enfermedad de Boca, Mano y Pie/prevención & control , Enfermedad de Boca, Mano y Pie/inmunología , Ratones , Vacunas Virales/inmunología , Epítopos Inmunodominantes/inmunología , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Femenino , Epítopos de Linfocito T/inmunología , Proteínas de la Cápside/inmunología , Proteínas de la Cápside/genética , Enterovirus/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Enterovirus Humano A/inmunología , Enterovirus Humano A/genética , Inmunogenicidad Vacunal , Inmunidad Celular , Inmunidad Humoral

RESUMEN

BACKGROUND: The increasing incidence of hand, foot, and mouth disease (HFMD) associated with Coxsackievirus A6 (CVA6) has become a very significant public health problem. The aim of this study is to investigate the recombination, geographic transmission, and evolutionary characteristics of the global CVA6. METHODS: From 2019 to 2022, 73 full-length CVA6 sequences were obtained from HFMD patients in China and analyzed in combination with 1032 published whole genome sequences. Based on this dataset, the phylogenetic features, recombinant diversity, Bayesian phylodynamic characteristics, and key amino acid variations in CVA6 were analyzed. RESULTS: The four genotypes of CVA6, A, D, E, and F, are divided into 24 recombinant forms (RFs, RF-A - RF-X) based on differences in the P3 coding region. The eastern China region plays a key role in the dissemination of CVA6 in China. VP1-137 and VP1-138 are located in the DE loop on the surface of the CVA6 VP1 protein, with the former being a highly variable site and the latter having more non-synonymous substitutions. CONCLUSIONS: Based on whole genome sequences, this study contributes to the CVA6 monitoring, early warning, and the pathogenic mechanism by studying recombination diversity, geographical transmission characteristics, and the variation of important amino acid sites.

Asunto(s)

Evolución Molecular , Genotipo , Enfermedad de Boca, Mano y Pie , Filogenia , Recombinación Genética , Humanos , China/epidemiología , Enfermedad de Boca, Mano y Pie/virología , Enfermedad de Boca, Mano y Pie/epidemiología , Genoma Viral , Secuenciación Completa del Genoma , Enterovirus/genética , Enterovirus/clasificación , Enterovirus/aislamiento & purificación , Variación Genética , Teorema de Bayes

RESUMEN

Hand, Foot, and Mouth Disease (HFMD) is an infectious disease that primarily affects young children. In densely populated Jiangsu Province in China, the impact of extreme meteorological factors on HFMD is a concern. We aimed to examine the association between extreme meteorological variables and HFMD infection risk using daily HFMD infections and meteorological data from 2010 to 2017 in Jiangsu Province. We used distributed lag non-linear model (DLNM) to analyze the data, which can effectively capture the nuanced non-linear dynamics and lag effects in the relationship between HFMD and extreme meteorological factors. Comparing the 10th and 90th percentiles of meteorological variables with their respective median values, our results showed that extremely low temperatures and high humidity were significantly associated with increased HFMD infection risk. The greatest effect of extremely low temperatures was observed at a lag of 1-2 days, elevating the risk by 18 âˆ¼ 33% (RR = 1.18 âˆ¼ 1.33). Extremely high humidity was found to increase the risk of infection, starting at a lag of 4 days. In contrast, extremely high temperatures, low humidity, and high wind speed were associated with reduced risk of infection at lag of 0-12 days, with the range of RR values being 0.60-0.98 for extremely high temperatures, 0.69-0.89 for extremely low humidity, and 0.84-0.98 for extremely high wind speed respectively. Our findings suggest that extreme meteorological factors can significantly impact the incidence of HFMD in Jiangsu Province, and highlight the need for effective public health protection measures during the periods of extreme meteorological condition, particularly for vulnerable populations.