Epidemical and etiological study on hand, foot and mouth disease following EV-A71 vaccination in Xiangyang, China

AbstractCoxsackievirus A6 (CV-A6) and Coxsackievirus A10 (CV-A10) have been emerging as the prevailing serotypes and overtaking Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) in most areas as main pathogens of hand, foot and mouth disease (HFMD) in China since 2013. To investigate whole etiological spectrum following EV-A71 vaccination of approximate 40,000 infants and young children in Xiangyang, enteroviruses were serotyped in 4415 HFMD cases from October 2016 to December 2017 using Real Time and conventional PCR and cell cultures. Of the typeable 3201 specimen, CV-A6 was the predominant serotype followed by CV-A16, CV-A10, CV-A5, CV-A2 and EV-A71 with proportions of 59.54%, 15.31%, 11.56%, 4.56%, 3.78% and 3.03%, respectively. Other 12 minor serotypes were also detected. The results demonstrated that six major serotypes of enteroviruses were co-circulating, including newly emerged CV-A2 and CV-A5. A dramatic decrease of EV-A71 cases was observed, whereas the total cases remained high. Multivalent vaccines against major serotypes are urgently needed for control of HFMD.

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Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6: A Preliminary Report from Istanbul

Polish Journal of Microbiology ◽

10.33073/pjm-2019-016 ◽

2019 ◽

Vol 68 (2) ◽

pp. 165-171

Author(s):

AYSE N. CEYLAN ◽

OZDEN TUREL ◽

BILGE SUMBUL GULTEPE ◽

ELIF INAN ◽

AYSEL VEHAPOGLU TURKMEN ◽

...

Keyword(s):

Preliminary Report ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Rt Pcr ◽

Coxsackievirus A16 ◽

Specific Primers ◽

Enterovirus A71 ◽

Coxsackievirus A6 ◽

The World ◽

Foot And Mouth

Hand, foot, and mouth disease (HFMD) is caused by various serotypes of Enterovirus genus. Coxsackievirus A16 (CV-A16) and enterovirus A71 (EV-A71) were known to be the only responsible agents for these epidemics; however, this opinion was challenged after the detection that coxsackievirus A6 (CV-A6) was the responsible species for the outbreak in Finland in 2008. HFMD is frequently seen in Turkey, and no detailed study on its clinical and microbiological epidemiology has previously been reported. The present study addresses this question. Twenty-seven patient samples collected between 2015 and 2017 were included in the study. Typing was conducted by RT-PCR and the sequencing applied directly to patient’s samples and as well as to the viral cultures with pan-enterovirus and serotype-specific primers. The presence of Enterovirus in 12 of 27 HFMD samples was shown with RT-PCR. The causative agent for three of these 12 samples was CV-A16, one of the most frequent two serotypes around the world, and the remaining nine samples was CV-A6. The findings of the study are relevant since it pertains to the molecular epidemiology of HFMD in Turkey, a gateway country where different serotypes might be circulating and transmitted. The findings also support the notion that CV-A6 cases are rising in number, which has caused more severe clinical features and widespread rashes in recent outbreaks.

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Clinical characteristics and managements of severe hand, foot and mouth disease caused by enterovirus A71 and coxsackievirus A16 in Shanghai, China

BMC Infectious Diseases ◽

10.1186/s12879-019-3878-6 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 5

Author(s):

Kang Cai ◽

Yizhong Wang ◽

Zhongqin Guo ◽

Huiju Yu ◽

Huajun Li ◽

...

Keyword(s):

Clinical Characteristics ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Coxsackievirus A16 ◽

Enterovirus A71 ◽

Foot And Mouth

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RSAD2 and AIM2 Modulate Coxsackievirus A16 and Enterovirus A71 Replication in Neuronal Cells in Different Ways That May Be Associated with Their 5′ Nontranslated Regions

Journal of Virology ◽

10.1128/jvi.01914-17 ◽

2017 ◽

Vol 92 (6) ◽

Cited By ~ 2

Author(s):

Thinesshwary Yogarajah ◽

Kien Chai Ong ◽

David Perera ◽

Kum Thong Wong

Keyword(s):

Viral Replication ◽

Neuronal Cells ◽

Neuroblastoma Cells ◽

Foot And Mouth Disease ◽

Neurological Complications ◽

Mouth Disease ◽

Host Responses ◽

Coxsackievirus A16 ◽

Enterovirus A71 ◽

Foot And Mouth

ABSTRACT Coxsackievirus A16 (CV-A16) and enterovirus A71 (EV-A71) are closely related enteroviruses that cause the same hand, foot, and mouth disease (HFMD), but neurological complications occur only very rarely in CV-A16 compared to EV-A71 infections. To elucidate host responses that may be able to explain these differences, we performed transcriptomic analysis and real-time quantitative PCR (RT-qPCR) in CV-A16-infected neuroblastoma cells (SK-N-SH), and the results showed that the radical S -adenosylmethionine domain containing 2 (RSAD2) was the highest upregulated gene in the antimicrobial pathway. Increased RSAD2 expression was correlated with reduced viral replication, while RSAD2 knockdown cells were correlated with increased replication. EV-A71 replication showed no apparent correlation to RSAD2 expressions. Absent in melanoma 2 (AIM2), which is associated with pyroptotic cell death, was upregulated in EV-A71-infected neurons but not in CV-A16 infection, suggesting that the AIM2 inflammasome played a significant role in suppressing EV-A71 replication. Chimeric viruses derived from CV-A16 and EV-A71 but containing swapped 5′ nontranslated regions (5′ NTRs) showed that RSAD2 expression/viral replication and AIM2 expression/viral replication patterns may be linked to the 5′ NTRs of parental viruses. Differences in secondary structure of internal ribosomal entry sites within the 5′ NTR may be responsible for these findings. Overall, our results suggest that CV-A16 and EV-A71 elicit different host responses to infection, which may help explain the apparent lower incidence of CV-A16-associated neurovirulence in HFMD outbreaks compared to EV-A71 infection. IMPORTANCE Although coxsackievirus A16 (CV-A16) and enterovirus A17 (EV-A71) both cause hand, foot, and mouth disease, EV-A71 has emerged as a leading cause of nonpolio, enteroviral fatal encephalomyelitis among young children. The significance of our research is in the identification of the possible differing and novel mechanisms of CV-A16 and EV-A71 inhibition in neuronal cells that may impact viral neuropathogenesis. We further showed that viral 5′ NTRs may play significant roles in eliciting different host response mechanisms.

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Divergent Pathogenic Properties of Circulating Coxsackievirus A6 Associated with Emerging Hand, Foot, and Mouth Disease

Journal of Virology ◽

10.1128/jvi.00303-18 ◽

2018 ◽

Vol 92 (11) ◽

Cited By ~ 11

Author(s):

Shao-Hua Wang ◽

Ao Wang ◽

Pan-Pan Liu ◽

Wen-Yan Zhang ◽

Juan Du ◽

...

Keyword(s):

Mouse Model ◽

Viral Protein ◽

Northeast China ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Promising Target ◽

Enterovirus A71 ◽

Coxsackievirus A6 ◽

Foot And Mouth ◽

Cultured Human Cells

ABSTRACTCoxsackievirus A6 (CV-A6) is an emerging pathogen associated with hand, foot, and mouth disease (HFMD). Its genetic characterization and pathogenic properties are largely unknown. Here, we report 39 circulating CV-A6 strains isolated in 2013 from HFMD patients in northeast China. Three major clusters of CV-A6 were identified and related to CV-A6, mostly from Shanghai, indicating that domestic CV-A6 strains were responsible for HFMD emerging in northeast China. Four full-length CV-A6 genomes representing each cluster were sequenced and analyzed further. Bootscanning tests indicated that all four CV-A6-Changchun strains were most likely recombinants between the CV-A6 prototype Gdula and prototype CV-A4 or CV-A4-related viruses, while the recombination pattern was related to, yet distinct from, the strains isolated from other regions of China. Furthermore, different CV-A6 strains showed different capabilities of viral replication, release, and pathogenesis in a mouse model. Further analyses indicated that viral protein 2C contributed to the diverse pathogenic abilities of CV-A6 by causing autophagy and inducing cell death. To our knowledge, this study is the first to report lethal and nonlethal strains of CV-A6 associated with HFMD. The 2C protein region may play a key role in the pathogenicity of CV-A6 strains.IMPORTANCEHand, foot, and mouth disease (HFMD) is a major and persistent threat to infants and children. Besides the most common pathogens, such as enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16), other enteroviruses are increasingly contributing to HFMD. The present study focused on the recently emerged CV-A6 strain. We found that CV-A6 strains isolated in Changchun City in northeast China were associated with domestic origins. These Changchun viruses were novel recombinants of the CV-A6 prototype Gdula and CV-A4. Our results imply that measures to control CV-A6 transmission are urgently needed. Further analyses revealed differing pathogenicities in strains isolated in a neonatal mouse model. One of the possible causes has been narrowed down to the viral protein 2C, using phylogenetic studies, viral sequences, and direct tests on cultured human cells. Thus, the viral 2C protein is a promising target for antiviral drugs to prevent CV-A6-induced tissue damage.

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Longitudinal study on enterovirus A71 and coxsackievirus A16 genotype/subgenotype replacements in hand, foot and mouth disease patients in Thailand, 2000–2017

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2018.12.020 ◽

2019 ◽

Vol 80 ◽

pp. 84-91 ◽

Cited By ~ 8

Author(s):

Pirom Noisumdaeng ◽

Achareeya Korkusol ◽

Jarunee Prasertsopon ◽

Kantima Sangsiriwut ◽

Kulkanya Chokephaibulkit ◽

...

Keyword(s):

Longitudinal Study ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Coxsackievirus A16 ◽

Enterovirus A71 ◽

Foot And Mouth

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First isolation and genomic characterization of enterovirus A71 and coxsackievirus A16 from hand foot and mouth disease patients in the Lao PDR

New Microbes and New Infections ◽

10.1002/nmi2.63 ◽

2014 ◽

Vol 2 (6) ◽

pp. 170-172 ◽

Cited By ~ 3

Author(s):

V.H. Nguyen ◽

B. Sibounheuang ◽

K. Phommasone ◽

M. Vongsouvath ◽

P.N. Newton ◽

...

Keyword(s):

Lao Pdr ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Coxsackievirus A16 ◽

Enterovirus A71 ◽

Foot And Mouth ◽

Genomic Characterization

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Clinical and Etiological Characteristics of Atypical Hand-Foot-and-Mouth Disease in Children from Chongqing, China: A Retrospective Study

BioMed Research International ◽

10.1155/2015/802046 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Xiang Yan ◽

Zhen-Zhen Zhang ◽

Zhen-Hua Yang ◽

Chao-Min Zhu ◽

Yun-Ge Hu ◽

...

Keyword(s):

Enterovirus 71 ◽

Foot And Mouth Disease ◽

Good Prognosis ◽

Mouth Disease ◽

Coxsackievirus A16 ◽

Neurologic Involvement ◽

Coxsackievirus A6 ◽

Foot And Mouth ◽

Two Peaks ◽

Epidemiological Characteristics

Background. Hand-foot-and-mouth disease (HFMD) is a disease that had similar manifestations to chickenpox, impetigo, and measles, which is easy to misdiagnose and subsequently causes delayed therapy and subsequent epidemic. To date, no study has been conducted to report the clinical and epidemiological characteristics of atypical HFMD.Methods. 64 children with atypical HFMD out of 887 HFMD children were recruited, stool was collected, and viral VP1 was detected.Results. The atypical HFMD accounted for 7.2% of total HFMD in the same period (64/887) and there were two peaks in its prevalence in nonepidemic seasons. Ten children (15.6%) had manifestations of neurologic involvement, of whom 4 (6.3%) were diagnosed with severe HFMD and 1 with critically severe HFMD, but all recovered smoothly. Onychomadesis and desquamation were found in 14 patients (21.9%) and 15 patients (23.4%), respectively. The most common pathogen was coxsackievirus A6 (CV-A6) which accounted for 67.2%, followed by nontypable enterovirus (26.6%), enterovirus 71 (EV-A71) (4.7%), and coxsackievirus A16 (A16) (1.5%).Conclusions. Atypical HFMD has seasonal prevalence. The manifestations of neurologic involvement in atypical HFMD are mild and usually have a good prognosis. CV-A6 is a major pathogen causing atypical HFMD, but not a major pathogen in Chongqing, China.

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