|Group:||Group IV ((+)ssRNA)|
Enterovirus 71 (EV71) is a virus of the genus Enterovirus in the Picornaviridae family notable for its etiological role in epidemics of severe neurological diseases in children. It was first isolated and characterized from cases of neurological disease in California in 1969. Enterovirus 71 infrequently causes polio-like syndrome permanent paralysis.
This virus is a member of the enterovirus species A. This virus appears to have evolved only recently with the first known strain isolated in 1965. It was associated with an outbreak of neurological disease in the United States in 1969. It spread then to Europe with outbreaks there in Bulgaria (1975) and Hungary (1978). It has since spread to various countries in Asia where it has been responsible for several outbreaks, most recently in Cambodia (2012).
The strains fall into six genogroups named A to F. Both the B and C genogroups have been subdivided into B0-B5 and C1-C5. The genogroup C appears to have evolved ~1970 while the A and B taxa evolved prior to this. Genogroup D was identified in India only and genogroups E and F in Africa only. Phylogenetic studies performed on partial sequences of viruses from India suggest that additional genogroups exist.
An analysis of strains isolated in Europe (Austria, France and Germany) showed that the clades C1b and C2b originated in 1994 (95% confidence interval 1992.7-1995.8) and 2002 (95% confidence interval 2001.6-2003.8) respectively.
The basic reproductive number (R0) for enterovirus 71 (EV71) was estimated to a median of 5.48 with an interquartile range of 4.20 to 6.51.
"The Enterovirus 71 (EV71) infection may be asymptomatic or it may cause diarrhea, rashes, and hand, foot and mouth disease (HFMD). However, EV71 also has the potential to cause severe neurological disease. To date, little is known about the molecular mechanisms of the host response to EV71 infection. [...] EV71 infection led to increases in the level of mRNAs encoding chemokines, proteins involved in protein degradation, complement proteins, and proapoptosis proteins."
"Enterovirus 71 (EV71), one of the major causative agents for hand, foot and mouth disease (HFMD), is sometimes associated with severe central nervous system diseases. In 1997, in Malaysia and Japan, and in 1998 in Taiwan, there were HFMD epidemics involving sudden death among young children, and EV71 was isolated from the HFMD patients, including the fatal cases. The nucleotide sequences of each EV71 isolate were determined and compared by phylogenetical analysis. EV71 strains from previously reported epidemics belonged to genotype A-1, while those from recent epidemics could be divided into two genotypes, A-2 and B."
"Ever since the 1980s, large and small EV71 epidemics caused by distinct genotypes have occurred in Asian countries and regions sharing trade with China. In Hong Kong, sporadic EV71 infections with incidences of monoplegia were reported in 1987, and a fatal case was documented in 2001. A large outbreak of HFMD due to EV71 infection occurred in Taiwan in 1998, including 129,106 case reports, 405 children with severe complications, and more than 80 deaths. After 1998, smaller EV71 epidemics occurred almost annually in Taiwan, primarily associated with EV71 viruses of genotypes C2 and B4. In Malaysia, EV71 outbreaks occurred in 1997 and 2000, mainly associated with genotypes B3 and B4. Since 1997, EV71 epidemics (genotypes B and C) have been reported annually in Singapore, with genotype B4 forming the predominant causative agent of a large outbreak in 2000 (5). In Korea, an EV71 epidemic in 2000 was caused by a relatively new genotype, C3, which has only rarely been identified outside of Korea in recent years (10). Thus, the EV71 genotypes of these HFMD epidemics seem to be regionally and temporally unrestricted."
|This article is outdated. (May 2013)|
There is no antiviral agent known to be effective in treating EV71 infection. However, Sinovac Biotech Ltd., a leading pharmaceutical company in China, conducted an experimental trial for an EV71 vaccination, which was completed in March 2013. Sinovac has submitted its drug candidate to the Beijing Drug Administration and is awaiting approval. The vaccine was administered to approximately 10,000 children between the ages of 6 and 35 months. Of the placebo group, there were 30 cases of hand, foot, and mouth disease (HFMD) reported, and 41 cases of any EV71-associated illness. This can be compared to only 3 cases of HFMD and eight cases of any EV71-related illness reported in the vaccine group. Participants were surveilled from day 56 until the end of the 14-month experiment period, in addition to checkups at months five, eight, eleven, and fourteen. Other experimental vaccines and antiviral agents are being researched. For example, "both bovine and human lactoferrins were found to be potent inhibitors of EV71 infection" and "ribavirin could be a potential anti-EV71 drug."
A joint UK and Chinese team working at the UK's national synchrotron facility near Oxford determined the structure of EV71 in 2012. Researchers observed movements resembling breathing in the virus, and found that this accompanied the infection process, together with a small molecule picked up from the body's cells and used to switch state. This particular molecule must be discarded in order to start an infection, and new research will be aimed at creating a synthetic replica that would bond strongly to the virus and stop the infection process.
In June 2013, an outbreak of four cases was noted in Sydney. Approximately 100 more children are believed to have been infected, and a panel of doctors are monitoring the situation at present.
From April through July 2012, at least 64 children died and two survived from a disease affecting children under 7 years old in Cambodia. Most died within 24 hours and had exhibited symptoms including respiratory illnesses, fever and generalized neurological abnormalities. An initial sampling taken from 24 patients found that 15 tested positive for EV71 on July 6, 2012. The World Health Organization noted that the cause of the outbreak has not been fully solved and that more analysis was needed.
On 15 July 2012, it was announced that no further cases had been noted in Cambodia, and that the deaths were a result of a combination of infections with EV 71, Dengue fever, and Streptococcus suis  and the use of steroids in the treatment of the infections.
|Wikinews has related news: Highly contagious Hand, foot and mouth disease killing China's children|
HFMD was recognized in China in 1980s and EV71 was first isolated in China from HFMD vesicle fluid in 1987 by Zhi-Ming Zheng at Virus Research Institute, Hubei Medical University  From 1999 to 2004, there were no epidemics of hand, foot, and mouth disease in Shenzhen, People's Republic of China, but each year there were small, local outbreaks associated with only a few cases of neurological disease and no reported fatalities. Genetic analysis revealed 19 cases of EV71 among 147 children who had hand, foot, and mouth disease in Shenzhen during this time. Until 2008, no large EV71 epidemic had been reported on the Chinese mainland, but sporadic infections were common in the southeast coastal area as well as in inland regions, such as Beijing, Chongqing, and Jinan. From 1998 to 2004, the only EV71 viruses identified on mainland China belonged to the genotype C4, indicating far less variety in China than in Taiwan.
On May 3, 2008, Chinese health authorities reported a major outbreak of EV71 enterovirus in Fuyang city and other localities in Anhui, Zhejiang, and Guangdong provinces. As of May 3, 2008, 3736 cases occurring mainly in children were reported, with 22 dead and 42 critically ill. Some 415 new cases were reported in 24 hours in Fuyang City alone. As of May 5, 2008, 6,300 were sickened by the viral outbreak which killed another child, in Zhejiang raising the death toll to 26 children, with 1,198 other children affected in that province alone.
Specifically, an additional 5,151 cases were reported in Anhui province with scores more in 4 other provinces. 8,531 cases of children infected with hand-foot-mouth disease (HFMD) were reported in China. All the children infected were aged below 6, with most of them being under 2. As of May 7 contagious HFMD led to 28 deaths. Xinhua reported the number of people infected, also rose by 4000 to 15,799.
Enteroviruses were isolated from a total of 1,892 patients in this laboratory during this period. Of the virus isolates, enterovirus 71 (EV71) was diagnosed in 44.4% of the patients (132 of 297) in 1998, 2% (13 of 646) in 1999, and 20.5% (195 of 949) in 2000. Genetic analyses of the 5′-untranslated[clarification needed] and VP1 regions of EV71 isolates by reverse transcription-PCR and sequencing were performed to understand the diversity of EV71 in these outbreaks of HFMD. Most EV71 isolates from the 1998 epidemic belonged to genotype C, while only one-tenth of the isolates were genotype B. Interestingly, all EV71 isolates tested from 1999 to 2000 belonged to genotype B. This study indicated that two genogroups of EV71 capable of inducing severe clinical illness have been circulating in Taiwan. Furthermore, the predominant EV71 genotypes responsible for each of the two major HFMD outbreaks within the 3-year period in Taiwan were different.
Significant outbreaks of the Enterovirus 71 (EV71) occurred in 1998, 2000 and 2001 with 78 deaths in 1998, 25 in 2000 and 26 in 2001. There are two patterns observed in outbreaks of the virus where they may be small with occasional cases resulting in death or they are severe with a high fatality rate. The 1998 outbreak came in two waves to Taiwan. The first wave reached its peak of fatalities in the week of June 7 with cases in all four regions of Taiwan. There were approximately 405 severe cases and 91% of fatal cases were children of under the age of five. After further investigation into the fatalities among children 16% were six months or younger, 43% were from seven to twelve months meaning it was more fatal for children under the age of one. 65 out of 78 patients died from pulmonary edema or haemorrhage making it the most lethal effect which results from the virus. The second wave occurred in the week of October 4 and had fewer cases that were more confined to Southern Taiwan. Total number of cases of Hand Foot and Mouth Disease (HFMD) and herpangina in Taiwan was 129,106.
Development and detection
The outbreaks of the Enterovirus 71 in Taiwan and the number of cases and fatalities that resulted became an indication of the significance of the threat of the virus. New anti-viral drugs should be developed and vaccination of children under five years old should be considered in areas the virus is more susceptive. In July 1989 a sentinel surveillance system for infectious diseases was established in Taiwan by Disease, Surveillance and Quarantine Service, Ministry of Health of Taiwan. The sentinel surveillance system is physician based and has approximately 850 Taiwanese physicians participating from various regions all over Taiwan. Public health officers contact the physicians on a weekly basis collecting disease information and on the occasion where there is a suspected outbreak of an infectious disease they are responsible for public notification. After the observed outbreak of HFMD and herpangina in Malaysia in 1997, they were included in the detection system.
In March 1998, under the sentinel surveillance system, it was noticed that there was an increasing amount of HFMD cases and herpangina in Taiwan. By the end of April that year, numbers of cases involving children HFMD had increased significantly. Due to the presence of a possible threat of an epidemic a warning was released on May 12 for the virus and preventative measures were advised to the public such as practicing better hygiene and isolating infected children. Although public notification had been given and preventatives taken, the number of HFMD cases continued to rise. On May 29 another report system, based on hospitals rather than just physicians, was developed in response to this where all severe and fatal cases were more carefully monitored from 597 hospital and medical centres.
Exact reasons behind the outbreaks are hard to and yet to be defined however through the reporting systems developed, detection of the virus is of large significance and gives way for further study and investigation. Possible reasons behind the developments of the outbreaks are that the virus may have mutated with increased virulence made it more easily contractible or that the population and genetics became more susceptible to contraction of the disease. Studies for serial serum antibody titers to the Enterovirus 71 in blood samples taken yearly from 81 children born in 1988 was conducted from 1989 to 1994 and 1997 to 1999. They discovered an increase in EV71 seroconversion (increased susceptibility to the disease) from 3% to 11% from 1989 to 1997 and by 1997 68% of the children had evidence of being infected by the virus. The virus was also evident in HFMD patients from as early on as 1981. Other studies conducted in early 1999 showed that half the adult population of Taiwan had antibodies against the enterovirus 71 prior to the 1998 outbreak meaning the population of children were more susceptible to the virus. It is possible that prior to the outbreak in 1998 there were severe and fatal cases that went unrecognised as EV71 cases in children who died of unexplained illnesses and studies are still ongoing.
Vietnam recorded 63780 cases of hand, foot and mouth disease in the first seven month of 2012. According to Tran Minh Dien, vice director of the National Hospital for Children about 58.7% percent were caused by EV71 
- Enterovirus 68, a similar, related virus also first isolated in California in the 1960s
- Herpangina, mouth blisters that can be caused by enteroviruses
- Lin TY, Chu C, Chiu CH (October 2002). "Lactoferrin inhibits enterovirus 71 infection of human embryonal rhabdomyosarcoma cells in vitro". J. Infect. Dis. 186 (8): 1161–4. doi:10.1086/343809. PMID 12355368.
- "Change of Major Genotype of Enterovirus 71 in Outbreaks of Hand-Foot-and-Mouth Disease in Taiwan between 1998 and 2000" (PDF). Retrieved 2012-07-28.
- Laboratory Investigation of a Suspected Enterovirus 71 Outbreak
- Bessaud M, et al. (March 2014). "Molecular Comparison and Evolutionary Analyses of VP1 Nucleotide Sequences of New African Human Enterovirus 71 Isolates Reveal a Wide Genetic Diversity". PLoS ONE 9 (3): e90624. doi:10.1371/journal.pone.0090624. PMC 3944068. PMID 24598878.
- Mirand A, Schuffenecker I, Henquell C, Billaud G, Jugie G, Falcon D, Mahul A, Archimbaud C, Terletskaia-Ladwig E; et al. (2009). "Phylogenetic evidence for a recent spread of two populations of human enterovirus 71 in European countries". J Gen Virol 91 (9): 2263–2277. doi:10.1099/vir.0.021741-0.
- Nishimura Y, Shimizu H (2012). "Cellular receptors for human enterovirus species A.". Front Microbio 3: 105. doi:10.3389/fmicb.2012.00105.
- Ma E, Fung C, Yip SH, Wong C, Chuang SK, Tsang T (Aug 2011). "Estimation of the basic reproduction number of enterovirus 71 and coxsackievirus A16 in hand, foot, and mouth disease outbreaks". Pediatr Infect Dis J 30 (8): 675–9. doi:10.1097/INF.0b013e3182116e95. PMID 21326133.
- Shih SR, Stollar V, Lin JY, Chang SC, Chen GW, Li ML (October 2004). "Identification of genes involved in the host response to enterovirus 71 infection". J. Neurovirol. 10 (5): 293–304. doi:10.1080/13550280490499551. PMID 15385252.
- Shimizu H, Utama A, Yoshii K, et al. (February 1999). "Enterovirus 71 from fatal and nonfatal cases of hand, foot and mouth disease epidemics in Malaysia, Japan and Taiwan in 1997–1998". Jpn. J. Infect. Dis. 52 (1): 12–5. PMID 10808253.
- Gross, Charles. "Sinovac Files NDA for EV71 Vaccine, Filing Accepted by Beijing Drug Administration". Benzinga. Retrieved 30 May 2013.
- Walsh, Nancy. "Vaccine Blocks Hand, Foot, Mouth Disease". MedPage Today. Retrieved May 30, 2013.
- Zhu, Feng-Cai; Liang, Zheng-Lun; Li, Xiu-Ling; Ge, Heng-Ming; Meng, Fan-Yue; Mao, Qun-Ying; Zhang, Yun-Tao; Hu, Yue-Mei; Zhang, Zhen-Yu; Li, Jing-Xin; Gao, Fan; Chen, Qing-Hua; Zhu, Qi-Yan; Chu, Kai; Wu, Xing; Yao, Xin; Guo, Hui-Jie; Chen, Xiao-Qin; Liu, Pei; Dong, Yu-Ying; Li, Feng-Xiang; Shen, Xin-Liang; Wang, Jun-Zhi. "Immunogenicity and safety of an enterovirus 71 vaccine in healthy Chinese children and infants: a randomised, double-blind, placebo-controlled phase 2 clinical trial". The Lancet 381: 1037–1045. doi:10.1016/S0140-6736(12)61764-4.
- Tung WS, Bakar SA, Sekawi Z, Rosli R (2007). "DNA vaccine constructs against enterovirus 71 elicit immune response in mice". Genet Vaccines Ther 5: 6. doi:10.1186/1479-0556-5-6. PMC 3225814. PMID 17445254.
- Li ZH, Li CM, Ling P, et al. (March 2008). "Ribavirin reduces mortality in enterovirus 71-infected mice by decreasing viral replication". J. Infect. Dis. 197 (6): 854–7. doi:10.1086/527326. PMID 18279075.
- Amos, J. (17 February 2013). "Diamond to shine light on infections". BBC News. Retrieved 18 February 2013.
- "Flu drug 'shows promise' in overcoming resistance". BBC News. 21 February 2013. Retrieved 24 February 2013.
- "Fatal fears over 'modern polio'". 7News. 19 June 2013. Retrieved 19 June 2013.
- Kwok, Yenni (5 July 2012). "Mystery illness claims dozens of Cambodian children". CNN. Retrieved 8 July 2012.
- "Officials make break in baffling disease killing Cambodian children". CNN. 8 July 2012. Retrieved 8 July 2012.
- "Mystery illness in Cambodia solved, doctors say". CNN.com. Retrieved 2012-07-28.
- Zheng ZM, Zhang JH, Zhu WP, He PJ (1989). "First isolation of enterovirus type 71 from vesicle fluid of an adult patient with hand-foot-mouth disease in China". Virologica Sinica 4 (4): 375–382.
- Zheng, Z. M.; He, P. J.; Caueffield, D.; Neumann, M.; Specter, S.; Baker, C. C.; Bankowski, M. J. (1995). "Enterovirus 71 isolated from China is serologically similar to the prototype E71 BrCr strain but differs in the 5'-noncoding region". Journal of medical virology 47 (2): 161–167. doi:10.1002/jmv.1890470209. PMID 8830120.
- "China on alert as virus spreads". BBC News. May 3, 2008.
- China orders heightened efforts to stop deadly virus AP News
- "China virus toll continues rise". BBC News. May 5, 2008.
- "www.inthenews.co.uk, Hand-foot-mouth epidemic continues to infect children across China". Inthenews.co.uk. Retrieved 2012-07-28.
- 6,300 sick, 26 dead in China viral outbreak
- "news.xinhuanet.com, Xinhua's tally: Death toll of hand-foot-mouth disease rises to 28 in China". News.xinhuanet.com. 2008-05-07. Retrieved 2012-07-28.
- "28 Chinese children die from virus". The Australian.
- Lin, Tzou-Yien (March 2003). "Enterovirus 71 outbreaks, Taiwan: Occurrence and Recognition". Emerging Infectious Diseases 9: 291–293. doi:10.3201/eid0903.020285. Retrieved 2012-09-20.
- Ho, Monto (23 September 1999). "An Epidemic of Enterovirus 71 in Taiwan". The New England Journal of Medicine 341: 929–935. doi:10.1056/nejm199909233411301.
- Wu, Trong-Neng (May–June 1999). "Sentinel Surveillance for Enterovirus 71, Taiwan, 1998". Emerging Infectious Diseases 5 (3): 458–460. doi:10.3201/eid0503.990321.
- "WPRO | Hand, Foot and Mouth Disease (HFMD)". Wpro.who.int. Retrieved 2012-07-28.
- "Bệnh TCM tăng 10 lần so với năm trước-Benh tay chan mieng |Suc khoe". Hn.24h.com.vn. Retrieved 2012-07-28.