• Digital PCR
• Enterovirus A
• Hand, Foot, and Mouth Disease
• Wastewater surveillance

• Hand, Foot and Mouth Disease/epidemiology
• Hand, Foot and Mouth Disease/virology
• Wastewater/virology
• Serogroup
• Japan/epidemiology
• Enterovirus/isolation & purification
• Enterovirus/genetics
• Humans
• Epidemiological Monitoring
• Environmental Monitoring/methods

• COVID‐19
• Epstein–Barr virus
• Monkeypox
• Sars‐COV‐2
• condyloma acuminatum
• cytomegalovirus
• focal epithelial hyperplasia
• herpes simplex virus
• human herpes virus
• human papillomavirus
• oral mucosa
• varicella zoster virus
• virus

• Humans
• Mouth Mucosa/virology
• Mouth Diseases/virology
• Mouth Diseases/microbiology
• Virus Diseases/virology

• Enterovirus
• epidemiology
• hand-foot-mouth disease
• outbreak
• surveillance
• vaccine

• Humans
• Hand, Foot and Mouth Disease/prevention & control
• Hand, Foot and Mouth Disease/epidemiology
• Hand, Foot and Mouth Disease/virology
• Enterovirus/isolation & purification
• Enterovirus/classification
• Global Health
• Viral Vaccines/immunology
• Enterovirus Infections/prevention & control
• Enterovirus Infections/epidemiology
• Enterovirus Infections/virology
• Epidemiological Monitoring
• Child, Preschool

• EV71
• cytokine storm
• macrophage
• ornithine
• severe HFMD

• Animals
• Ornithine
• Hand, Foot and Mouth Disease/immunology
• Mice
• Arginine/metabolism
• Disease Models, Animal
• Humans
• Cytokines/metabolism
• Spermine/metabolism
• Female
• Enterovirus A, Human/immunology
• Male
• Mice, Inbred C57BL
• Severity of Illness Index

• Blood-brain barrier
• Central nervous system
• Enterovirus
• Enterovirus A71

• Humans
• Blood-Brain Barrier
• Enterovirus Infections
• Enterovirus/physiology
• Central Nervous System
• Biological Transport

• Biosensors
• Coxsackievirus A16 (CVA16)
• Diagnotic tools
• Enterovirus 71 (EV71)
• Hand, foot, and mouth disease (HFMD)
• Optical absorption spectroscopy
• Outbreak

• Child
• Humans
• Enterovirus A, Human
• Hand, Foot and Mouth Disease/diagnosis
• Enterovirus/genetics
• Polymerase Chain Reaction
• Spectrum Analysis

• Coxsackievirus A-16
• HFMD
• enterovirus A-71

• Enterovirus A71
• enterovirus
• hand-foot-mouth disease
• internal ribosomal entry site
• single-chain variable fragment

• TUFF42/2565 Thailand Science Research and Innovation Fundamental Fund
• 2564 Thammasat University Research Unit in Molecular Pathogenesis and Immunology of Infectious Diseases

• China
• Enteroviruses 71 (EV71)
• amino acid variation
• hand, foot and mouth disease (HFMD)
• phylogenetics
• phylogeographic dynamics
• recombination

• Key Research and development program of Shanxi Province

• Epidemiological characteristic
• Hand-foot-and-mouth disease
• Innate immune response
• Sequelae
• Treatment

• Animals
• Foot-and-Mouth Disease/complications
• Foot-and-Mouth Disease/epidemiology
• Hand, Foot and Mouth Disease/epidemiology
• Enterovirus
• Enterovirus Infections
• Disease Outbreaks
• China/epidemiology
• Enterovirus A, Human

• NO. 82273695 National Natural Science Foundation of China
• NO. 82002147 National Natural Science Foundation of China
• NO. 82073618 National Natural Science Foundation of China
• NO. 2019M662543 China Postdoctoral Science Foundation
• NO. 21A310026 Key Scientific Research Project of Henan Institution of Higher Education

• HFMD EV-A71
• NtAb vaccine

Hand, foot, and mouth disease (HFMD) has become one of the most common infectious diseases in China. Before 2016, the primary causal serotypes were enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16). Following the introduction of EV-A71 vaccines in China since 2016, the situation could change. CV-A6 has recently replaced EV-A71 and CV-A16 in some areas of China. However, the epidemiological characteristics of central China remain unknown.

To investigate the clinical symptoms and pathogen spectrum of HFMD in Shiyan City, central China, in recent years.

The epidemiological, clinical, and laboratory data from HFMD cases reported to the Shiyan Center for Disease Control and Prevention between January 2016 and December 2020 were analyzed. 196 throat swab specimens were collected from hospitalized HFMD patients between January 2018 and December 2020. To detect and genotype enteroviruses, real-time reverse transcription-polymerase chain reaction and sequencing of the 5'-untranslated region were used. In Shiyan, 168 laboratory-confirmed HFMD cases were studied using a logistic regression model to determine the effect of predominant enterovirus serotypes. Based on the logistic regression model, the least absolute shrinkage and selection operator model was used to analyze the correlation between CV-A6 infection and various clinical characteristics in HFMD patients in Shiyan.

From 2016 to 2020, 35840 HFMD cases were reported in Shiyan. The number of cases decreased by 48.4% from 2016 to 2017. Approximately 1.58-fold increases were found in 2018 and 2019 when compared to the previous year, respectively. In 2020, a decrease of about 85.5% was reported when compared to 2019. The most common serotypes shifted from EV-A71 and CV-A16 (about 60%-80% in 2016 and 2018) to others (more than 80.0% in 2017, 2019, and 2020). EV-A71 lost its dominance in 2017 in Shiyan. Among 196 confirmed HFMD cases, 85.7% tested positive for enterovirus, with CV-A6 being the most common serotype (121/168, 72.0%). The positive rates for CV-A16 and CV-A10 were 4.8% and 3.0%, respectively. There was no EV-A71 discovered. Infection with CV-A6 was linked to fever, myocardial damage, increased creatine kinase MB isoenzyme, and lactate dehydrogenase levels.

CV-A6 was the most common enterovirus serotype in Shiyan City, replacing EV-A71 and CV-A16 as the HFMD pathogen. Developing vaccines against CV-A6 or multiple pathogens, as well as rising CV-A6 surveillance, will help prevent HFMD in central China.

• Hand, foot, and mouth disease
• Coxsackievirus A6
• Enterovirus
• Prevalence serotype
• Fever
• Myocardial damage

•

A stable EV-A71 virus vector was created to generate chimeric strains expressing capsid protein genes of EV-A71 C5 and CA16.

• Enterovirus A71
• Picornaviridae
• antiviral agent
• biochemistry
• foot and mouth disease
• genetics
• hand
• microbiology
• molecular biology
• molecular epidemiology
• vaccine
• virology

• Enterovirus 71
• Hand foot and mouth disease
• polypeptide vaccine

• enterovirus 71
• foot
• hand
• mouth disease
• phylogeographic analysis
• spatial transmission

• National Natural Science Foundation of China
• Ministry of Science and Technology of China

Hand, foot, and mouth disease (HFMD) is highly prevalent in East and Southeast Asia. It particularly affects children under five years of age. The most common causative agents are coxsackieviruses A6 and A16, and enterovirus A71 (EV71). The clinical presentation is usually mild and self-limited, but, in some cases, severe and fatal complications develop. To date, no specific therapy or worldwide vaccine is available. In general, viral infection invokes both antibody and cell-mediated immune responses. Passive immunity transfer can ameliorate the severe symptoms of diseases such as COVID-19, influenza, MERS, and SARS. Hyperimmune plasma (HIP) from healthy donors with high anti-EV71 neutralizing titer were used to transfuse confirmed EV71-infected children with neurological involvement (n = 6). It resulted in recovery within three days, with no neurological sequelae apparent upon examination 14 days later. Following HIP treatment, plasma chemokines were decreased, whereas anti-inflammatory and pro-inflammatory cytokines gradually increased. Interestingly, IL-6 and G-CSF levels in cerebrospinal fluid declined sharply within three days. These findings indicate that HIP has therapeutic potential for HFMD with neurological complications. However, given the small number of patients who have been treated, a larger cohort study should be undertaken. Successful outcomes would stimulate the development of anti-EV71 monoclonal antibody therapy.

• EV71
• hand, foot, and mouth disease
• hyperimmune plasma treatment
• neurological complication

Enterovirus A71 (EV-A71) and coxsackievirus A16 (CA16) are major etiological agents of hand foot and mouth disease (HFMD) in children, which may result in fatal neurological complications. The development of safe, cost effective vaccines against HFMD, especially for use in developing countries, is still a top public health priority. We have successfully generated a stable, cold-adapted, temperature sensitive/conditional lethal EV-A71 through adaptive culturing in Vero cells at incrementally lower cultivation temperatures. An additional 40 passages at an incubation temperature of 28 °C, and a temperature reversion study at an incubation temperature of 37 °C and 39.5 °C, reveals the virus’s phenotypic and genetic stability at the predefined culture conditions. Six unique mutations (two in noncoding regions and four in nonstructural protein-coding genes) in combination may have contributed to its stable phenotype and inability to fully revert to its original wild phenotype. The safety and immunogenicity of this stable, cold-adapted, temperature sensitive/conditional lethal EV-A71 was performed in six monkeys. None of the inoculated monkeys developed any obvious clinical illness except one which developed a transient spike of fever. No gross postmortem lesion or abnormal histological finding was noted for all monkeys at autopsy. No virus was reisolated although EV-A71 specific RNA was detected in serum samples collected on both day 4 and day 8 postinoculation. Only EV-A71 RNA and viral antigen were detected in the spleen homogenate and peripheral blood mononuclear cells, respectively, collected on day 4. The two remaining monkeys developed good humoral immune response on day 14 and day 30 post-inoculation.

• attenuation
• candidate vaccine
• coxsackievirus A16
• enterovirus A71
• temperature sensitive and conditional lethal

• Acute pulmonary edema
• Enterovirus 71
• Fluid management
• Hand, foot, and mouth disease
• Pulse indicator continuous cardiac output

Enterovirus A71 (EV-A71) has emerged as a clinically important neurotropic virus following poliovirus eradication. Recent studies have shown that human tonsillar epithelial cell lines (UT-SCC-60A and UT-SCC-60B) were susceptible to EV-A71, suggesting that human tonsillar crypt epithelium could be important in EV-A71 pathogenesis. However, the mechanism about how EV-A71 infects the upper oro-digestive tract remains largely unclear. In this study, we demonstrated that the human tonsillar epithelial cells infected with EV-A71 underwent apoptotic, in which cytochrome c was released from the mitochondria to the cytosol and caspase-9 was activated, while caspase-2 and -8 were not cleaved or activated during the infection. A selective inhibitor of caspase-9, Z-LEHD-FMK, inhibited the cleavage of the executioner caspase-3 and -7, indicating that only mitochondria-mediated intrinsic apoptotic pathway was activated in EV-A71-infected tonsillar epithelial cells. No evidence of pyroptosis or necroptosis was involved in the cell death. EV-A71 infection induced interferon, pro-inflammatory cytokines and chemokines, including IFN-β, IL-6, CCL5, and TNF-α in tonsillar epithelial cells, which may play a critical role in EV-A71-caused herpangina. Our data indicated that the induction of the cytokines was partially regulated by the mitogen-activated protein kinases (MAPKs) signaling pathway. The findings unveiled the host response to EV-A71 and its regulation mechanism, and will further our understanding the significance about the tonsillar crypt epithelium as the initial and primary portal in viral pathogenesis for EV-A71 infection.

• Apoptosis
• Cell Line
• Cytochromes c/metabolism
• Cytokines/metabolism
• Enterovirus A, Human/physiology
• Epithelial Cells/pathology
• Epithelial Cells/virology
• Gene Expression Regulation
• Humans
• Palatine Tonsil/pathology
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Virus Replication

• National Natural Science Foundation of China (CN)
• National Natural Science Foundation of China

Hand, foot, and mouth disease (HFMD) is a common global epidemic. From 2008 onwards, many HFMD outbreaks caused by coxsackievirus A6 (CV-A6) have been reported worldwide. Since 2013, with a dramatically increasing number of CV-A6-related HFMD cases, CV-A6 has become the predominant HFMD pathogen in mainland China. Phylogenetic analysis based on the VP1 capsid gene revealed that subtype D3 dominated the CV-A6 outbreaks. Here, we performed a large-scale (near) full-length genetic analysis of global and Chinese CV-A6 variants, including 158 newly sequenced samples collected extensively in mainland China between 2010 and 2018. During the global transmission of subtype D3 of CV-A6, the noncapsid gene continued recombining, giving rise to a series of viable recombinant hybrids designated evolutionary lineages, and each lineage displayed internal consistency in both genetic and epidemiological features. The emergence of lineage –A since 2005 has triggered CV-A6 outbreaks worldwide, with a rate of evolution estimated at 4.17 × 10⁻³ substitutions site^-1 year⁻¹ based on a large number of monophyletic open reading frame sequences, and created a series of lineages chronologically through varied noncapsid recombination events. In mainland China, lineage –A has generated another two novel widespread lineages (–J and –L) through recombination within the enterovirus A gene pool, with robust estimates of occurrence time. Lineage –A, –J, and –L infections presented dissimilar clinical manifestations, indicating that the conservation of the CV-A6 capsid gene resulted in high transmissibility, but the lineage-specific noncapsid gene might influence pathogenicity. Potentially important amino acid substitutions were further predicted among CV-A6 variants. The evolutionary phenomenon of noncapsid polymorphism within the same subtype observed in CV-A6 was uncommon in other leading HFMD pathogens; such frequent recombination happened in fast-spreading CV-A6, indicating that the recovery of deleterious genomes may still be ongoing within CV-A6 quasispecies. CV-A6-related HFMD outbreaks have caused a significant public health burden and pose a great threat to children’s health; therefore, further surveillance is greatly needed to understand the full genetic diversity of CV-A6 in mainland China.

• Coxsackievirus A6
• evolutionary dynamics
• foot and mouth disease
• genetic recombination
• hand
• pathogenicity
• phylogeny
• whole-genome analysis

Acute flaccid myelitis (AFM) is an acute paralysis syndrome defined by a specific inflammation of the anterior horn cells of the spinal cord. From 2014, worrying waves of life-threatening AFM consecutive to enterovirus infection (EV-D68 and EV-A71) have been reported. We describe 10 children displaying an AFM with an EV infection, the treatments performed and the 1 to 3-years follow-up. Two groups of patients were distinguished: 6 children (“polio-like group”) had severe motor disability whereas 4 other children (“brainstem group”) displayed severe brainstem weakness requiring ventilation support. Electrodiagnostic studies (n = 8) support the presence of a motor neuronopathy associated to myelitis. The best prognosis factor seems to be the motor recovery after the first 4 weeks of the disease.

• EV-A71
• EV-D68
• children
• enterovirus
• myelitis

Background: Enterovirus 71 (EV71) is the main pathogen that causes severe hand, foot, and mouth disease with fatal neurological complications. However, its neurovirulence mechanism is still unclear. Candidate virulence sites were screened out at structural protein VP1, but the function of these candidate virulence sites remains unclear. Several studies have shown that autophagy is associated with viral replication. However, the relationship between VP1 and autophagy in human neurons has not been studied. Methods: A recombinant virus—SDLY107-VP1, obtained by replacing the VP1 full-length gene of the SDLY107 strain with the VP1 full-length gene of the attenuated strain SDJN2015-01—was constructed and tested for replication and virulence. We then tested the effect of the recombinant virus on autophagy in nerve cells. The effect of autophagy on virus replication was detected by western blot and plaque test. Finally, the changes of mTOR signaling molecules during EV71 infection and the effect of mTOR on virus replication at the RNA level were detected. Results: Viral recombination triggered virulence attenuation. The replication ability of recombinant virus SDLY107-VP1 was significantly weaker than that of the parent strain SDLY107. The SDLY107 strain could inhibit autophagic flux and led to accumulation of autophagosomes, while the SDLY107-VP1 strain could not cause autophagosome accumulation. The synthesis of EV71 RNA was inhibited by inhibiting mTOR. Conclusions: Replacement of VP1 weakened the replication ability of virulent strains and reduced the level of autophagy in nerve cells. This autophagy facilitates the replication of virulent strains in nerve cells. VP1 is an important neurovirulence determinant of EV71, which affects virus replication by regulating cell autophagy. mTOR is a key molecule in this type of autophagy.

• EV71
• VP1
• autophagy
• virus replication

• Amino Acid Sequence
• Autophagosomes
• Autophagy
• Biomarkers
• Capsid Proteins/chemistry
• Capsid Proteins/metabolism
• Cell Line, Tumor
• Enterovirus A, Human/physiology
• Enterovirus Infections/metabolism
• Enterovirus Infections/virology
• Host-Pathogen Interactions
• Humans
• Recombination, Genetic
• Signal Transduction
• TOR Serine-Threonine Kinases/metabolism
• Virus Replication

Hand, foot and mouth disease (HFMD) is a serious infectious disease, which has become a public health problem. Previous studies have shown that temperature may influence the incidence of HFMD, but most only focus on single city and the results are highly heterogeneous. Therefore, a multicity study was conducted to explore the association between temperature and HFMD in different cities and search for modifiers that influence the heterogeneity.

We collected daily cases of childhood HFMD (aged 0–5 years) and meteorological factors of 21 cities in Guangdong Province in the period of 2010–2013. Distributed lag non-linear model (DLNM) with quasi-Poisson was adopted to quantify the effects of temperature on HFMD in 21 cities. Then the effects of each city were pooled by multivariate meta-analysis to obtain the heterogeneity among 21 cities. Potential city-level factors were included in meta-regression to explore effect modifiers.

A total of 1,048,574 childhood cases were included in this study. There was a great correlation between daily childhood HFMD cases and temperature in each city, which was non-linear and lagged. High heterogeneity was showed in the associations between temperature and HFMD in 21 cities. The pooled temperature-HFMD association was peaking at the 79th percentile of temperature with relative risk (RR) of 2.474(95% CI: 2.065–2.965) as compared to the median temperature. Latitude was the main modifier for reducing the heterogeneity to 69.28% revealed by meta-analysis.

There was a strong non-linear and lagged correlation between temperature and HFMD. Latitude was strongly associated with the relationship between temperature and HFMD. Meanwhile, it had an effect on modifying the relationship. These findings can conducive to local governments developing corresponding preventive measures.

• Distributed lag non-linear model
• Hand, foot and mouth disease
• Multivariate meta-analysis
• Two-stage analysis

Enteroviruses (EVs) are responsible for extremely large-scale, periodic epidemics in pediatric cohorts, particularly in East and Southeast Asia. Clinical presentation includes a diverse disease spectrum, including hand-foot and mouth disease (HFMD), aseptic meningitis, encephalitis, acute flaccid paralysis, and acute flaccid myelitis. HFMD is predominantly attributable to EV-A types, including the major pathogen EV-A71, and coxsackieviruses, particularly CV-A6, CV-A16, and CV-A10. There have been multiple EV-A71 outbreaks associated with a profound burden of neurological disease and fatal outcomes in Asia since the early 1980s. Efficacious vaccines against EV-A71 have been developed in China but widespread pediatric vaccination programs have not been introduced in other countries. Encephalitis, as a consequence of complications arising from HFMD infection, leads to damage to the thalamus and medulla oblongata. Studies in Vietnam suggest that myoclonus is a significant indicator of central nervous system (CNS) complications in EV-A71-associated HFMD cases. Rapid response in HFMD cases in children is imperative to prevent the progression to a CNS infection; however, prophylactic and therapeutic agents have not been well established internationally, therefore surveillance and functional studies including development of antivirals and multivalent vaccines is critically important to reduce disease burden in pediatric populations.

• central nervous system complications
• encephalitis
• enterovirus A71
• hand-foot and mouth disease
• molecular characterization

• Developed Countries
• Developing Countries
• Enterovirus/isolation & purification
• Enterovirus Infections/complications
• Enterovirus Infections/virology
• Hand, Foot and Mouth Disease/epidemiology
• Hand, Foot and Mouth Disease/virology
• Humans
• Incidence
• Japan/epidemiology
• Nervous System Diseases/epidemiology
• Nervous System Diseases/virology

Enterovirus A71 (EV-A71) is one of the common causative pathogens for hand foot and mouth disease (HFMD) affecting young children. HFMD outbreak can result in a substantial pediatric hospitalization and burden the healthcare services, especially in less-developed countries. Since the initial epidemic of predominantly EV-A71 in California in 1969, the high prevalence of HFMD in the Asia-pacific region and elsewhere around the world represents a significant morbidity in this age group. With the advent of rapid and accurate diagnostic tools, there has been a dramatic increase in the number of laboratory-confirmed EV-A71 infection over the past two decades. The population, cultural, and socioeconomic diversity among countries in the Asia-Pacific region all influence the transmission and morbidity associated with HFMD. This review summarizes the current state of epidemiology of EV-A71 in Asia-Pacific countries based on the most recent epidemiological data and available information on the prevalence and disease burden. This knowledge is important in guiding the prevention, control and future research on vaccine development of this highly contagious disease of significant socioeconomic implications in public health.

• Asia-Pacific region
• Enterovirus A71
• Molecular epidemiology

• RNA viruses
• plaque phenotype
• quasispecies
• spontaneous mutations
• virulence

• Animals
• DNA-Directed RNA Polymerases/genetics
• Evolution, Molecular
• Humans
• Quasispecies/genetics
• RNA Viruses/genetics
• RNA Viruses/pathogenicity
• Viral Proteins/genetics
• Virulence

• 2019 Sunway University Internal Grant (2019) for Center for Virus and Vaccine Research (CVVR)

• Adolescent
• Child
• Child, Preschool
• China/epidemiology
• Disease Outbreaks/statistics & numerical data
• Enterovirus/genetics
• Enterovirus/pathogenicity
• Female
• Hand, Foot and Mouth Disease/epidemiology
• Hand, Foot and Mouth Disease/virology
• Humans
• Infant
• Male
• Phylogeny
• Serotyping
• Young Adult

• Medical Scientific Research Foundation of Guangdong Province (A2018455)
• Shenzhen Basic Research Grants (JCYJ20150402111430635)
• Sanming Project of Medicine in Shenzhen (SZSM201606088)

• Coxsackievirus A16
• Enterovirus 71
• Epidemiology
• HFMD

• early warning system
• hand foot and mouth disease
• pediatric

• Adolescent
• Age Factors
• Algorithms
• Animals
• Blood Glucose
• C-Reactive Protein/analysis
• Child
• Child, Hospitalized
• Child, Preschool
• Clinical Deterioration
• Consciousness
• Female
• Foot-and-Mouth Disease/pathology
• Heart Rate
• Humans
• Infant
• Infant, Newborn
• Intensive Care Units, Pediatric
• Male
• ROC Curve
• Retrospective Studies
• Severity of Illness Index

• Animals
• Antiviral Agents/therapeutic use
• Benzofurans/therapeutic use
• Cell Line
• Cell Membrane/drug effects
• Cell Membrane/metabolism
• Cell Membrane/ultrastructure
• Cell Membrane/virology
• Enterovirus A, Human/drug effects
• Enterovirus A, Human/pathogenicity
• Enterovirus A, Human/physiology
• Enterovirus A, Human/ultrastructure
• Enterovirus Infections/drug therapy
• Enterovirus Infections/metabolism
• Enterovirus Infections/pathology
• Enterovirus Infections/virology
• Host-Pathogen Interactions/drug effects
• Humans
• Mice
• Mice, Knockout
• Microscopy, Electron, Transmission
• Mitochondrial Membranes/drug effects
• Mitochondrial Membranes/metabolism
• Mitochondrial Membranes/ultrastructure
• Mitochondrial Membranes/virology
• Nerve Tissue Proteins/antagonists & inhibitors
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/metabolism
• Neurons/drug effects
• Neurons/metabolism
• Neurons/ultrastructure
• Neurons/virology
• Prohibitins
• Proteomics/methods
• RNA Interference
• Repressor Proteins/antagonists & inhibitors
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Specific Pathogen-Free Organisms
• Survival Analysis
• Virus Internalization/drug effects
• Virus Replication/drug effects

• National Medical Research Council

• EV71
• Enterovirus 71
• and mouth disease
• foot
• hand
• host interactions
• immune response
• pathogenesis

• IS-HPU-1112-10117 Department of Health
• MC_PC_15096 Medical Research Council
• G116/194 Medical Research Council
• RP-PG-0108-10048 Department of Health
• EME/12/205/28 Department of Health

• acute flaccid paralysis
• encephalitis
• enterovirus A
• meningitis, sequencing

Hand, foot and mouth disease (HFMD) is one of the highest reported infectious diseases with several outbreaks across the world. This study aimed at describing epidemiological characteristics, investigating spatio-temporal clustering changes, and identifying determinant factors in different clustering areas of HFMD.

Descriptive statistics was used to evaluate the epidemic characteristics of HFMD from 2009 to 2015. Spatial autocorrelation and spatio-temporal cluster analysis were used to explore the spatial temporal patterns. An autologistic regression model was employed to explore determinants of HFMD clustering.

The incidence rates of HFMD ranged from 54.31/10 million to 318.06/10 million between 2009 and 2015 in Hunan. Cases were mainly prevalent in children aged 5 years and even younger, with an average male-to-female sex ratio of 1.66, and two epidemic periods in each year. Clustering areas gathered in the northern regions in 2009 and in the central regions from 2010 to 2012. They moved to central-southern regions in 2013 and 2014 and central-western regions in 2015. The significant risk factors of HFMD clusters were rainfall (OR = 2.187), temperature (OR = 4.329) and humidity (OR = 2.070). The protect factor was wind speed (OR = 0.258).

The HFMD incidence from 2009 to 2015 in Hunan showed a new spatiotemporal clustering tendency, with the shifting trend of clustering areas toward south and west. Meteorological factors showed a strong association with HFMD clustering, which may assist in predicting future spatial-temporal clusters.

The online version of this article (10.1186/s12879-017-2742-9) contains supplementary material, which is available to authorized users.

• Autologistic regression model
• Determinants
• HFMD
• Spatial autocorrelation
• Spatio-temporal analysis
• Tendency analysis

• EV-A71
• Enterovirus 71
• encephalitis
• hand foot and mouth disease
• pulmonary oedema

The objective of this study was to identify potential risk factors for severe hand, foot and mouth disease (HFMD). In this case-control study, 459 severe HFMD patients and 246 mild HFMD patients from Guangdong province and Henan province, China were included. Data comprising demographic characteristics, clinical symptoms and signs, laboratory findings and other factors were collected. Univariate analysis revealed 30 factors associated with severe cases. Further multivariate analysis indicated four independent risk factors: fatigue (p < 0.01, odd ratio [OR] = 204.7), the use of glucocorticoids (p = 0.03, OR = 10.44), the use of dehydrant drugs (p < 0.01, OR = 73.7) and maculopapular rash (p < 0.01, OR = 84.4); and one independent protective factor: herpes or ulcers in mouth (p = 0.01, OR = 0.02). However, more systematic research and validation are needed to understand the underlying risk factors for severe HFMD.

There are a variety of enteroviruses (EV) that can cause hand, foot and mouth disease (HFMD), and the major pathogens include enterovirus 71 (EV71) and coxasckievirus A16 (CVA16). EV71 and CVA16 have attracted much attention for their high prevalence and pathogenicity, and disease surveillance and vaccine development are mainly concentrated on them. EV71 can cause serious harm to children with HFMD, especially the damage to the nervous system such as aseptic meningitis, brain stem encephalitis and paralytic disease, or even lead to death. However, in recent years, due to the epidemic of EV71 and CVA16, people have established an immune barrier through natural infection in a certain degree. Although there is no cross protection between types, the immune protection against the relevant type can persist for a long time. Thus, the number of HFMD cases caused by EV71 and CVA16 shows a decreasing trend, while the epidemic of HFMD caused by other EV exhibits an upward trend. Further studies found that non-EV71 and non-CVA16 EV are very complex, and there are also differences in EV prevalence each year, which makes the development, evolution and control of HFMD become complicated. At present, there is no enough attention paid to the sporadic virus in the HFMD epidemic, and a complete research system for non-EV71 and non-CVA16 EV has not formed. Therefore, it is necessary to strengthen the monitoring of multiple non-EV71 and non-CVA16 EV, further investigate their pathogenicity and genetic characteristics, and evaluate the relative frequency and biological hazard of infection. In this review, we summarize a variety of EV changes, molecular evolution, as well as typical epidemics, which may provide clues to the development of antiviral drugs and vaccines, and prevention and control of HFMD.

• Hand, foot and mouth disease
• Epidemic situation
• Enterovirus
• Evolution trend

• hand
• foot and mouth disease
• ev-a71
• cv-a16
• epidemiology

• Asia/epidemiology
• Disease Outbreaks/statistics & numerical data
• Enterovirus
• Hand, Foot and Mouth Disease/epidemiology
• Hand, Foot and Mouth Disease/virology
• Humans
• Risk Factors
• Rural Population/statistics & numerical data
• Urban Population/statistics & numerical data

• Enteroviruses
• Epidemiology
• HFMD
• Vaccine

• Global Health
• Hand, Foot and Mouth Disease/epidemiology
• Hand, Foot and Mouth Disease/prevention & control
• Humans
• Immunization/methods
• Viral Vaccines/immunology
• Viral Vaccines/isolation & purification

Literature shows inconsistency in meteorological effects on Hand, foot, and mouth disease (HFMD) in different cities. This multi-city study aims to investigate the meteorological effects on pediatric HFMD occurrences and the potential effect modification by geographic factors.

Based on daily time-series data in eight major cities in Guangdong, China during 2009–2013, mixed generalized additive models were employed to estimate city-specific meteorological effects on pediatric HFMD. Then, a random-effect multivariate meta-analysis was conducted to obtain the pooled risks and to explore heterogeneity explained by city-level factors.

There were a total of 400,408 pediatric HFMD cases (children aged 0–14 years old) with an annual incidence rate of 16.6 cases per 1,000 children, clustered in males and children under 3 years old. Daily average temperature was positively associated with pediatric HFMD cases with the highest pooled relative risk (RR) of 1.52 (95 % CI: 1.30–1.77) at the 95th percentile of temperature (30.5 °C) as compared to the median temperature (23.5 °C). Significant non-linear positive effects of high relative humidity were also observed with a 13 % increase (RR = 1.13, 95 % CI: 1.00–1.28) in the risk of HFMD at the 99th percentile of relative humidity (86.9 %) as compared to the median value (78 %). The effect estimates showed geographic variations among the cities which was significantly associated with city’s latitude and longitude with an explained heterogeneity of 32 %.

Daily average temperature and relative humidity had non-linear and delayed effects on pediatric HFMD and the effects varied across different cities. These findings provide important evidence for comprehensive understanding of the climatic effects on pediatric HFMD and for the authority to take targeted interventions and measures to control the occurrence and transmission of HFMD.

The online version of this article (doi:10.1186/s12879-016-1846-y) contains supplementary material, which is available to authorized users.

• China
• Hand, foot, and mouth disease
• Meteorological factors
• Mixed generalized additive model