HFMD is an acute contagious disease in children caused by enteroviruses. In recent years, the CV-A6 pathogen has become one of the dominant pathogens causing HFMD. However, our knowledge of this new pathogen's epidemiological and genetic characteristics still needs to be improved. In this paper, we review the epidemiological characteristics and genetic recombination of CV-A6, as well as the epidemiological status, epidemiological characteristics, and preventive and control measures of CV-A6 HFMD, to systematically describe the information related to CV-A6 HFMD, and to provide a scientific basis for the subsequent related research.

Jiaxin Li, Yaping Li, Yufeng Zhang, Huiling Deng. Current Status of Research on Coxsackievirus A6 Hand, Foot and Mouth Disease. International Journal of Frontiers in Medicine (2024), Vol. 6, Issue 7: 57-63. https://doi.org/10.25236/IJFM.2024.060710.

[1] Wang J, Guo Y S, Christakos G, et al. Hand, foot and mouth disease: spatiotemporal transmission and climate[J]. International Journal of Health Geographics, 2011, 10: 1-10.

[2] Yang S, Wu J, Ding C, et al. Epidemiological features of and changes in the incidence of infectious diseases in China in the first decade after the SARS outbreak: an observational trend study[J]. The Lancet Infectious Diseases, 2017, 17(7): 716-725.

[3] Di B, Zhang Y, Xie H, et al. Circulation of Coxsackievirus A6 in hand-foot-mouth disease in Guangzhou, 2010-2012[J]. Virology Journal, 2014, 11: 1-7.

[4] Blomqvist S, Klemola P, Kaijalainen S, et al. Co-circulation of coxsackieviruses A6 and A10 in hand, foot, and mouth disease outbreak in Finland[J]. Journal of Clinical Virology, 2010, 48(1): 49-54.

[5] Broccolo F, Drago F, Ciccarese G, et al. Severe atypical hand-foot-and-mouth disease in adults due to coxsackievirus A6: Clinical presentation and phylogenesis of CV-A6 strains[J]. Journal of Clinical Virology, 2019, 110: 1-6.

[6] Bian L, Wang Y, Yao X, et al. Coxsackievirus A6: a new emerging pathogen causing hand, foot, and mouth disease outbreaks worldwide[J]. Expert review of anti-infective therapy, 2015, 13(9): 1061-1071.

[7] Caro V, Guillot S, Delpeyroux F, et al. Molecular strategy for ‘serotyping’of human enteroviruses[J]. Journal of General Virology, 2001, 82(1): 79-91.

[8] Büttner C R, Spurný R, Füzik T, et al. Cryo-electron microscopy and image classification reveal the existence and structure of the coxsackievirus A6 virion[J]. Communications Biology, 2022, 5(1): 898.

[9] Puenpa J, Vongpunsawad S, Österback R, et al. Molecular epidemiology and the evolution of human coxsackievirus A6[J]. Journal of General Virology, 2016, 97(12): 3225-3231.

[10] Yuan J, Shen L, Wu J, et al. Enterovirus A71 proteins: structure and function[J]. Frontiers in Microbiology, 2018, 9: 286.

[11] Khan H, Khan A. Genome-wide population structure inferences of human coxsackievirus-A; insights the genotypes diversity and evolution[J]. Infection, Genetics and Evolution, 2021, 95: 105068.

[12] Rui Y, Su J, Wang H, et al. Disruption of MDA5-mediated innate immune responses by the 3C proteins of coxsackievirus A16, coxsackievirus A6, and Enterovirus D68[J]. Journal of Virology, 2017, 91(13): 10.1128/jvi. 00546-17.

[13] Wan-xue Z, Jue L I U. Research progress on the epidemiology of hand, foot and mouth disease caused by Coxsackievirus A6 [J]. Chinese Journal of Disease Control and Prevention, 2021, 25(5): 605-611.

[14] Wang H, Yu W, Xu T, et al. Molecular characteristic analysis for the VP1 region of coxsackievirus A6 strains isolated in Jiujiang area, China, from 2012 to 2013[J]. Medicine, 2019, 98(14): e15077.

[15] Li X, Xu X, Li J, et al. Preparation and immunoprotective effects of a virus-like particle candidate vaccine of the dominant epidemic D3 genotype coxsackievirus A6 in China[J]. Biosafety and Health, 2024, 6(01): 28-34. 

[16] Puenpa J, Saengdao N, Khanarat N, et al. Evolutionary and genetic recombination analyses of coxsackievirus A6 variants associated with hand, foot, and mouth disease outbreaks in Thailand between 2019 and 2022[J]. Viruses, 2022, 15(1): 73.

[17] Gaunt E, Harvala H, Österback R, et al. Genetic characterization of human coxsackievirus A6 variants associated with atypical hand, foot and mouth disease: a potential role of recombination in emergence and pathogenicity[J]. Journal of General Virology, 2015, 96(5): 1067-1079.

[18] Song Y, Zhang Y, Han Z, et al. Genetic recombination in fast-spreading coxsackievirus A6 variants: a potential role in evolution and pathogenicity[J]. Virus Evolution, 2020, 6(2): veaa048.

[19] Sinclair C, Gaunt E, Simmonds P, et al. Atypical hand, foot, and mouth disease associated with coxsackievirus A6 infection, Edinburgh, United Kingdom, January to February 2014[J]. Eurosurveillance, 2014, 19(12): 20745.

[20] Feng X, Guan W, Guo Y, et al. A novel recombinant lineage’s contribution to the outbreak of coxsackievirus A6-associated hand, foot and mouth disease in Shanghai, China, 2012-2013[J]. Scientific Reports, 2015, 5(1): 11700.

[21] Zhu Z, Zhu S, Guo X, et al. Retrospective seroepidemiology indicated that human enterovirus 71 and coxsackievirus A16 circulated wildly in central and southern China before large-scale outbreaks from 2008[J]. Virology Journal, 2010, 7: 1-6.

[22] Rui J, Luo K, Chen Q, et al. Early warning of hand, foot, and mouth disease transmission: a modeling study in China[J]. PLoS Neglected Tropical Diseases, 2021, 15(3): e0009233.

[23] Zeng H, Lu J, Yang F, et al. The increasing epidemic of hand, foot, and mouth disease caused by coxsackievirus-A6, Guangdong, China, 2017[J]. Journal of Infection, 2018, 76(2): 220-223.

[24] Foronda J L M, Jiao M M A D, Climacosa F M M, et al. Epidemiological and molecular characterization of Coxsackievirus A6 causing hand, foot, and mouth disease in the Philippines, 2012–2017[J]. Infection, Genetics and Evolution, 2023, 114: 105498.

[25] Song Y, Zhang Y, Ji T, et al. Persistent circulation of Coxsackievirus A6 of genotype D3 in China between 2008 and 2015[J]. Scientific Reports, 2017, 7(1): 5491.

[26] Pan K, Zhou K P, Xu J Q, et al. Pathogenic spectrum of enteroviruses and genetic characteristics of Coxsackievirus A6 in children with hand，foot，and mouth disease from 2018 to 2022 in Hubei province [J]. Chinese Journal of Vaccines and Immunization, 2023, 29(04):422-426.DOI:10. 19914/j. CJVI. 2023073.

[27] Zhang M, Chen X, Wang W, et al. Genetic characteristics of Coxsackievirus A6 from children with hand, foot and mouth disease in Beijing, China, 2017–2019[J]. Infection, Genetics and Evolution, 2022, 106: 105378.

[28] Shi Y, Ge Y, Ma W, et al. Genetic characterization of coxsackievirus A6 associated with hand, foot, and mouth disease in Anhui Province, China, 2017-2018[J]. Chinese Journal of Virology,2021,37(06):1326-1332.

[29] Tan ZhaoLin T Z L, Lv LiKun L L K, Li Li L L, et al. The genetic characteristics of Coxsackievirus A6 strains isolated in Tianjin from 2013-2017[J]. Journal of Pathogen Biology, 2018,13(11):1248-1252.

[30] ZHOU X, ZHOU Y, JIANG L, et al. Etiological surveillance of HFMD and the phylogenetic analysis of coxsackievirus A6 in Wenshan prefecture of Yunnan province, China, 2014 to 2018[J]. Chinese Journal of Microbiology and Immunology, 2021: 629-634.

[31] Su Z, Shi X, Zhang F, et al. Genome Sequence of a Human Coxsackievirus A6 Strain Isolated from a Severe Hand, Foot, and Mouth Disease Case in Qingdao, China, in 2017[J]. Microbiology Resource Announcements, 2020, 9(17): 10.1128/mra. 01449-19.

[32] Tikute S, Deshmukh P, Chavan N, et al. Emergence of Recombinant Subclade D3/Y in Coxsackievirus A6 Strains in Hand-Foot-and-Mouth Disease (HFMD) Outbreak in India, 2022[J]. Microorganisms, 2024, 12(3): 490.

[33] Luchs A, Azevedo L S, Souza E V, et al. Coxsackievirus A6 strains causing an outbreak of hand-foot-and-mouth disease in Northeastern Brazil in 2018[J]. Revista do Instituto de Medicina Tropical de Sao Paulo, 2022, 64: e16.

[34] Mizuta K, Tanaka S, Komabayashi K, et al. Phylogenetic and antigenic analyses of coxsackievirus A6 isolates in Yamagata, Japan between 2001 and 2017[J]. Vaccine, 2019, 37(8): 1109-1117.

[35] Li J, Zheng BY, Wang J F. Spatial-temporal heterogeneity of Hand, Foot and Mouth Disease in China from 2008 to 2018[J]. Journal of Geo-information Science, 2021, 23(3):419-430. 

[36] Wu Y, Wang T, Zhao M, et al. Spatiotemporal cluster patterns of hand, foot, and mouth disease at the province level in China, 2011–2018[J]. Plos one, 2022, 17(8): e0270061.

[37] Ji T, Han T, Tan X, et al. Surveillance, epidemiology, and pathogen spectrum of hand, foot, and mouth disease in China from 2008 to 2017[J]. Biosafety and Health, 2019, 1(01): 32-40.

[38] Broccolo F, Drago F, Ciccarese G, et al. Severe atypical hand-foot-and-mouth disease in adults due to coxsackievirus A6: Clinical presentation and phylogenesis of CV-A6 strains[J]. Journal of Clinical Virology, 2019, 110: 1-6.

[39] Hardin J, Haber R M. Onychomadesis: literature review[J]. British Journal of Dermatology, 2015, 172(3): 592-596.

[40] Zhao T S, Du J, Sun D P, et al. A review and meta‐analysis of the epidemiology and clinical presentation of coxsackievirus A6 causing hand‐foot‐mouth disease in China and global implications[J]. Reviews in medical virology, 2020, 30(2): e2087.

[41] Li Y, Xiong T, Meng Y, et al. Risk factors for severe hand, foot, and mouth disease infected with Coxsackievirus A6: A hospital‐based case‐control study[J]. Journal of Medical Virology, 2020, 92(12): 3144-3150.

[42] Zhao J, Jiang F, Zhong L, et al. Age patterns and transmission characteristics of hand, foot and mouth disease in China[J]. BMC Infectious Diseases, 2016, 16: 1-12.

[43] Wang L, Xu C, Wang J, et al. Spatiotemporal associations between hand, foot and mouth disease and meteorological factors over multiple climate zones[J]. International Journal of Biometeorology, 2023, 67(9): 1493-1504.

[44] Chen Y, Sun W, Ling F, et al. Seasonality and Meteorological Factors Associated With Different Hand, Foot, and Mouth Disease: Serotype-Specific Analysis From 2010 to 2018 in Zhejiang Province, China[J]. Frontiers in Microbiology, 2022, 13: 901508.

[45] He X, Dong S, Li L, et al. Using a Bayesian spatiotemporal model to identify the influencing factors and high-risk areas of hand, foot and mouth disease (HFMD) in Shenzhen[J]. PLoS Neglected Tropical Diseases, 2020, 14(3): e0008085.

[46] Meng Y, Xiong T, Zhao R, et al. Genome-wide association study identifies TPH2 variant as a novel locus for severe CV-A6-associated hand, foot, and mouth disease in Han Chinese[J]. International Journal of Infectious Diseases, 2020, 98: 268-274.

[47] Wang J, Jiang L, Zhang C, et al. The changes in the epidemiology of hand, foot, and mouth disease after the introduction of the EV-A71 vaccine[J]. Vaccine, 2021, 39(25): 3319-3323.

[48] Yang Z, Rui J, Qi L, et al. Study on the interaction between different pathogens of Hand, foot and mouth disease in five regions of China[J]. Frontiers in Public Health, 2022, 10: 970880.

[49] Chen F, Gong L, Ma W W, et al. Epidemiological characteristics and prevention and control measures of Hand-foot-mouth disease in Anhui，2013-2017 [J]. Modern Preventive Medicine, 2018, 45(17): 3084-3088+3097.

[50] Min N, Ong Y H B, Han A X, et al. An epidemiological surveillance of hand foot and mouth disease in paediatric patients and in community: A Singapore retrospective cohort study, 2013–2018[J]. PLoS Neglected Tropical Diseases, 2021, 15(2): e0008885.

[51] Wang Y, Xu C, Zhang S, et al. Development and evaluation of a deep learning approach for modeling seasonality and trends in hand-foot-mouth disease incidence in China[J]. Scientific Reports, 2019, 9(1): 8046.