[Study on the etiology of hand, foot and mouth disease (HFMD) in China].
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Molecular Epidemiology of Coxsackievirus A10 Associated With Hand, Foot and Mouth Disease From 2021 to 2024 in Shenzhen, China.
The study aimed to investigate epidemiological profile and molecular characteristics of coxsackievirus A10 (CVA10) associated with hand, foot and mouth disease (HFMD) in Shenzhen, China and comparatively analyze genomes of CVA10 strains related to differential clinical phenotypes. A total of 3170 clinical specimens collected between 2021 and 2024 were examined for CVA10 using real-time RT-PCR. Complete VP1 sequences and near-complete genome sequences of CVA10 were determined by RT-PCR methods and sequencing. Sequences were analyzed using a series of bioinformatics programs. Two (33.33%) out of 6 severe cases were infected with CVA10. The detection rate of CVA10 associated with mild HFMD ranged from 1.21% to 6.11% in 2021-2024, with an overall detection rate of 3.73%. There was no significant difference in the infection rate of CVA10 between males and females or different age groups. The CVA10 infections mainly occurred in Spring (March to May) and Summer (June to August) in Shenzhen. Of the 74 VP1 sequences determined, 71 (95.95%) of them were detected in the sub-genotype C2, 3 (4.05%) were assigned to the genotype D. Genomic sequence analysis indicated that the genotype D of CVA10 of this study derived from genetic recombination between CVA10 and CVA16 in 3A-3D coding region (nucleotide position: 5075-6896). Different variable sites were observed in the two CVA10 strains associated with different severe complications when compared to CVA10 strains associated with mild diseases. In conclusion, CVA10 associated with HFMD circulated at a low level in Shenzhen in 2021-2024, with C2 as the predominant genotype. Recombinant genotype D of CVA10 was introduced first to Shenzhen in 2024. The study emphasizes the importance of continuous molecular surveillance of CVA10.
Humans↗
Genetic Variation and Evolutionary Characteristics of Coxsackievirus B1: F3 Subtype Associated With Hand, Foot and Mouth Disease in China.
Coxsackievirus B1 (CV-B1) is primarily associated with meningitis but can also cause localized outbreaks of hand, foot, and mouth disease (HFMD). This study analyzed the genetic diversity of the VP1 gene in 39 strains of the CVB1 virus isolated from HFMD children across 15 provinces in China between 2010 and 2024, as well as 179 strains from 17 countries. Based on the average nucleotide difference of VP1 gene, we classified CVB1 virus into six genotypes A to F, Notably, genotype F is newly classified. Since 2010, genotype F guadually replaced genotype E as the dominant genotype in China and has further subdivided into three subtypes: F1, F2, and F3, with F3 being the most prevalent subtype in China currently. We specifically study the mild and severe cases within the F3 subtype. Temperature-sensitivity experiments revealed no differences between mild and severe cases of the F3 subtype, and they all belong to temperature-sensitive strains. Interestingly, we found that mild cases of the F3 subtype did not involve recombination, whereas all severe cases of the F3 subtype showed recombination with Coxsackievirus B4 (CVB4). CVB4 has consistently been the primary pathogen responsible for severe neonatal illnesses, suggesting that recombination between the F3 subtype and CVB4 may be associated with the development of severe HFMD. These findings provide fundamental scientific data for further investigation into the epidemiology and genetic characteristics of variants of Coxsackievirus B1 in China.
Humans↗
Hand, foot and mouth disease associated with coxsackievirus group B.
This study from Frankfurt, although similar to other reports with respect to clinical findings, presents further evidence of a varied etiology for hand, foot and mouth disease (HFMD). Of the 6 patients with HFMD, 5 ahd virologic evidence of coxsackievirus B5 infection, and 1 had definite evidence of coxsackievirus B2 infection. Our data suggest an etiologic association of coxsackievirus group B with HFMD.
Antibodies, Viral↗
Comparison of immunogenicity, safety, and efficacy of EVA71 vaccine in children: a systematic review and meta-analysis.
INTRODUCTION: Enterovirus 71 (EV-A71) is a principal cause of hand, foot, and mouth disease (HFMD), potentially leading to severe neurological complications in children. Inactivated EV-A71 vaccines have been introduced. This study compares the immunogenicity, safety, and efficacy of EV-A71 vaccines versus placebo in pediatric populations. RESEARCH DESIGN AND METHODS: Following a PROSPERO-registered protocol, RCTs involving EV-A71 in children were identified via PubMed, Scopus, Cochrane, and ClinicalTrials.gov. Two independent reviewers performed screening, extraction, and RoB assessments (RoB 2.0). RESULTS: Five phase III RCTs involving 36,659 children were included. EV-A71 vaccination significantly increased seropositivity across follow-up periods, including early (RR 5.8), medium-term (RR 3.09), and long-term (RR 2.95) response. Seroconversion was significantly higher in the vaccinated group (pooled RR 13.04, 95% CI 2.80-60.61; p < 0.001). Geometric mean titers, analyzed using the ratio of means approach, were significantly higher in the vaccinated group during early and medium-term follow-up. Vaccine efficacy against EV-A71-associated HFMD exceeded 98% (pooled RR 0.02, 95% CI 0.01-0.09; p = 0.0028; I2 = 50%). Solicited local and systemic adverse events were mild and comparable between groups. CONCLUSION: Inactivated EV-A71 vaccines robust immunogenicity, high clinical efficacy, and an acceptable safety profile in children. Future studies should explore long-term protection, booster schedules, and multivalent formulations against non-EV-A71 serotypes.
Humans↗
Epidemiological study of an "hand-foot-and-mouth disease" outbreak observed in Rome in the fall of 1973.
An outbreak of "hand-foot-and-mouth disease" (HFMD) occurred in Nov. 1973 in a nursery school. Sixty-seven children were studied, 15 of whom presented clinical signs of the disease. Sixty-two percent of the HFMD cases and 18% of asymptomatics were proved to be infected with Coxsackie virus A 16. The ratio of clinical to asymptomatic infection of nursery-school children with confirmed Coxsackie A 16 infection was 58%. The accidental diffusion of the infection led to the occurrence of secondary cases. This allowed to establish the incubation period of the illness at 8 to 12 days, for 3 individual cases where a single infecting contact in a very definite time could be documented. Fecal excretion of virus was demonstrable in 2 cases up to 10-20 days, while the duration of oral excretion appeared to be somewhat shorter. Evidence was also obtained showing that infectious virus could be spread by patients during the incubation period. Virus isolations were more easily obtained in suckling mice than in cell culture.
Adult↗
Neurovirulence in cynomolgus monkeys of enterovirus 71 isolated from a patient with hand, foot and mouth disease.
Six cynomolgus monkeys were inoculated subcutaneously with enteroviurs 71 (E71), isolated from the stools of a patient with hand, foot and mouth disease (HFMD). Clinical symptoms were observed in three of the six monkeys. One monkey showed complete paralysis of the lower extremities and two animals showed weakness in the hind limbs 4 to 7 days after inoculation. Lesions were found in the central nervous system (CNS) of all monkeys. Mild to moderate vascular lesions, perivascular cuffings, degeneration and disappearance of the neurons and meningial lymphocytic infiltration were observed in the grey and/or white matter of the spinal cord, medulla oblongata, cerebral cortex and brain stem. No virus was recovered from the CNS or liver of any of the six monkeys. However, serum neutralizing antibody titers had risen in monkeys inoculated with E71.
Animals↗
Dystrophin deficiency causes lethal muscle hypertrophy in cats.
Two 5-month-old male Domestic Shorthair littermates showed general skeletal muscle hypertrophy, multifocal submucosal lingual calcification with lingual enlargement, and excessive salivation. Both cats had a reduced level of activity, walked with a stiff gait, and tended to "bunny hop" when they ran. These clinical features were similar to those of previously reported dystrophin-deficient cats. Using multiple dystrophin antibodies, we found that the cats described in this report also showed marked dystrophin deficiency. The histopathology was remarkable for hypertrophy and splitting of fibers, and progressive accumulation of calcium deposits within the muscle. There was little or no endomysial fibrosis at 2 years of age. The natural history of dystrophin-deficiency in cats has not been described: both previous cats had been euthanized at 2 years of age prior to experiencing any life-threatening problems. At 6 months of age, one of the new cats developed megaesophagus because of severe progressive hypertrophy of the diaphragmatic muscles. The diaphragm completely occluded the esophagus, and the cat was euthanized for humane reasons. The second cat remained in good condition until age 18 months when it developed acute renal failure attributed to severe prolonged dehydration and hyperosmolality. The cat recovered after receiving supportive treatment but was unable to maintain fluid homeostasis. The insufficient water intake was attributed to glossal hypertrophy and dysfunction. At age 2 years, the cat received regular subcutaneous injections of low-sodium fluids to maintain proper hydration. The clinical consequence of dystrophin deficiency in cats is lethal muscle hypertrophy. We have called the feline disease "hypertrophic feline muscular dystrophy" (HFMD).
Animals↗
Coxsackievirus A6 on the rise: epidemiology, pathogenicity, evolutionary dynamics, and antiviral strategy.
SUMMARYIn recent years, coxsackievirus A6 (CVA6) has become a predominant cause of hand, foot, and mouth disease (HFMD) worldwide, surpassing enterovirus A71 (EV-A71) and CVA16. The rise of CVA6 is of particular public health concern due to its association with atypical and severe clinical presentations, including extensive vesiculobullous eruptions and neurological complications. These diverse and often non-classical manifestations, which also occur in adults, complicate clinical diagnosis and highlight the need for enhanced molecular surveillance. Furthermore, the potential impact of enteroviral infection during pregnancy and on neonatal outcomes remains an important clinical consideration. While both structural and non-structural proteins of CVA6 are known to contribute to viral virulence, the underlying pathogenic mechanisms are not fully understood. Continuous evolution of CVA6 through genetic variation and frequent recombination has led to the emergence of distinct lineages and recombinants, posing substantial challenges to the development of effective antivirals and vaccines. To address these gaps, this review systematically examines the global epidemiology, pathogenic mechanisms, evolutionary dynamics, current diagnostic tools, and antiviral strategies for CVA6. By integrating these perspectives, this work aims to inform public health preparedness and guide future research toward mitigating outbreaks driven by emerging recombinants and novel enterovirus serotypes.
Humans↗
Electron microscopic demonstration of virus particles in hand, foot and mouth disease.
Early skin and oral mucous membrane lesions of hand, foot and mouth disease (HFMD) were biopsied and investigated by light and electron microscopy. Histology showed spongiosis, intraepidermal splits indicating beginning vesicle formation, exocytosis of lymphoid cells and macrophages, and individual necrotic keratinocytes. Electron microscopy revealed naked viruses with a mean diameter of 24 nm which were arranged in sheets in the cytoplasm. Many keratinocyte nuclei contained tonofibrils. Cellular injury ranged from slight cytoplasmic edema to keratinocyte necrosis. Some nuclei showed dissolution of the nuclear membrane and dislocation of cytoplasm into the nucleus.
Biopsy↗
Intertypic Recombination Between Coxsackievirus A16 and Enterovirus A71 Structural and Non-Structural Genes Modulates Virulence and Protection Efficacy.
Background/Objectives: Enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16) are major causative agents of hand, foot and mouth disease (HFMD), often co-circulating and occasionally undergoing genetic recombination. While natural recombinants often involve genomic regions encoding non-structural proteins, their effects on replication and pathogenesis remain unclear. Methods: To address this, four chimera viruses (Chi-CCE, Chi-ECE, Chi-EEC, and Chi-CEC) were constructed with 5'UTR, capsid P1, and non-structural P2 and P3 genes, from CVA16 (denoted as C) or EV-A71 (denoted as E). These chimeras were tested for replication kinetics and cytopathic effects in rhabdomyosarcoma cells while in vivo virulence and protection efficacy were evaluated using a newborn BALB/c mouse model. Results: All chimeric viruses remained viable and exhibited higher replication than CVA16. In vivo, all chimeric viruses were avirulent except Chi-CCE and CVA16, which showed high virulence and viral titres in the brains and limbs of infected newborn mice. This suggests that 5'UTR and capsid P1 genes of CVA16 are critical genetic determinants of virulence. Notably, only the anti-inflammatory cytokine IL-10 was elevated, suggesting potential immune modulation during infection. Inactivated Chi-CCE immunisation conferred 100% protection against lethal CVA16 or mouse-adapted EV-A71 challenge revealing its potential as a bivalent vaccine candidate. Conclusions: Our study demonstrates that recombination between CVA16 and EV-A71 influences viral virulence and protection efficacy with implications for future development of multivalent vaccines.
coxsackievirus A16↗
Hand-foot-and-mouth disease: report of a case in Texas.
Coxsackie virus infections are highly contagious and can occur at epidemic levels within low socioeconomic populations. Since these diseases spread by contact, summer and fall occurrences increase significantly. A low grade fever and malaise are often related to non-specific viral infections. Hand-foot-and mouth disease (HFMD) is specifically caused by coxsackie virus.
Child, Preschool↗
Viral infections.
This article has concentrated on the etiology, pathogenesis, diagnosis, and treatment of viral infections of the hand. Some of these entities are quite common, but are often misdiagnosed. Herpes simplex appears to be the most common viral infection involving the hand. These and other viral infections can have much graver consequences in immunosuppressed patients. Recurrent episodes are common in herpetic and other viral infections. Health care workers have long been at risk, but improved compliance with prophylactic measures would seem to be decreasing the number of cases in this population. A plea has been made to disregard the term herpetic whitlow because it is an inaccurate description of the lesion and implies that an inappropriate type of treatment is required. Bacterial whitlows or felons require incision and drainage of the deep pulp space. Herpetic infections in this area do not. Less common infections such as cowpox, pseudocowpox (milkers nodules), ORF, and coxsackievirus (HFMD) infection of the hand have been brought to the attention of the reader. The bothersome warts caused by the human papillomavirus have been described and the systemic ramifications of hand-to-hand contact and hand injury causing more serious viral problems has been mentioned. A common thread in the care of the patient with these types of diseases is that an adequate history and physical remain invaluable in arriving at the correct diagnosis. With this correct diagnosis all of us, as physicians, then can easily abide by one of our basic principles Primum non nocere, "Let me help--but first let me do no harm."
Coxsackievirus Infections↗