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Enterovirus 71 (EV71), also known as Enterovirus A71 (EV-A71), is a
virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...
of the genus ''
Enterovirus ''Enterovirus'' is a genus of positive-sense single-stranded RNA virus An RNA virus is a virusother than a retrovirusthat has ribonucleic acid (RNA) as its genetic material. The nucleic acid is usually single-stranded RNA ( ssRNA) but it ma ...
'' in the ''
Picornaviridae Picornaviruses are a group of related nonenveloped RNA viruses which infect vertebrates including fish, mammals, and birds. They are viruses that represent a large family of small, positive-sense, single-stranded RNA viruses with a 30 nm i ...
'' family, notable for its role in causing epidemics of severe neurological disease and
hand, foot, and mouth disease Hand, foot, and mouth disease (HFMD) is a common infection caused by a group of enteroviruses. It typically begins with a fever and feeling generally unwell. This is followed a day or two later by flat discolored spots or bumps that may blis ...
in children. It was first isolated and characterized from cases of neurological disease in
California California is a U.S. state, state in the Western United States, located along the West Coast of the United States, Pacific Coast. With nearly 39.2million residents across a total area of approximately , it is the List of states and territori ...
in 1969. Enterovirus 71 infrequently causes
polio-like syndrome Polio-like syndrome is a general description of a group of symptoms which mimic polio, including rarely permanent paralysis. Various triggers have been found, including some viruses from the same virus group as polio: enterovirus 68, enterovirus 71 ...
permanent paralysis.


Evolution

This virus is a member of the enterovirus species A. Species A was formerly assigned to the genus ''
Rhinovirus The rhinovirus (from the grc, ῥίς, rhis "nose", , romanized: "of the nose", and the la, vīrus) is the most common viral infectious agent in humans and is the predominant cause of the common cold. Rhinovirus infection proliferates in tem ...
''. 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 then spread 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. Intra- and inter-typic recombination occur commonly in EV-A71 virus infections.Huang SW, Cheng D, Wang JR. Enterovirus A71: virulence, antigenicity, and genetic evolution over the years. J Biomed Sci. 2019 Oct 21;26(1):81. doi: 10.1186/s12929-019-0574-1. Review. Recombination can occur when at least two viral
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
s are present in the same host cell. The mechanism of recombination likely involves strand switching by the
RNA-dependent RNA polymerase RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand complementary to a given RNA template. This is in contrast to t ...
(copy-choice recombination), a mechanism demonstrated in
poliovirus A poliovirus, the causative agent of polio (also known as poliomyelitis), is a serotype of the species ''Enterovirus C'', in the family of ''Picornaviridae''. There are three poliovirus serotypes: types 1, 2, and 3. Poliovirus is composed of an ...
. In addition to being a source of sequence diversity, recombination in
RNA virus An RNA virus is a virusother than a retrovirusthat has ribonucleic acid (RNA) as its genetic material. The nucleic acid is usually single-stranded RNA ( ssRNA) but it may be double-stranded (dsRNA). Notable human diseases caused by RNA viruses ...
es appears to be an adaptation for repairing genome damage.


Virology

The receptors for EV71 and CVA16 have been identified as
P-selectin glycoprotein ligand-1 Selectin P ligand, also known as SELPLG or CD162 (cluster of differentiation 162), is a human gene. SELPLG codes for PSGL-1, the high affinity counter-receptor for P-selectin on myeloid cells and stimulated T lymphocytes. As such, it plays a crit ...
and scavenger receptor class B, member 2 (
SCARB2 Lysosomal integral membrane protein 2 (LIMP-2) is a protein that in humans is encoded by the ''SCARB2'' gene. LIMP-2 is expressed in brain, heart, liver, lung and kidney, mainly in the membrane of lysosome organelles; however, in cardiac muscle, LI ...
); both are transmembrane proteins. 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.


Treatment

There is no
antiviral Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do no ...
agent known to be effective in treating EV71 infection. However,
Sinovac Biotech Sinovac Biotech Ltd. () is a Chinese biopharmaceutical company based in Haidian District, Beijing that focuses on the research, development, manufacture, and commercialization of vaccines that protect against human infectious diseases. The comp ...
Ltd., a pharmaceutical company in China, conducted an experimental trial for an EV71 vaccination, which was completed in March 2013. In December 2015, the
China Food and Drug Administration The National Medical Products Administration (NMPA, , formerly the China Food and Drug Administration, or CFDA) was founded on the basis of the former State Food and Drug Administration (SFDA). In March 2013, the former regulatory body was rebra ...
(CFDA) approved the first EV71 vaccine. 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 Bovines (subfamily Bovinae) comprise a diverse group of 10 genera of medium to large-sized ungulates, including cattle, bison, African buffalo, water buffalos, and the four-horned and spiral-horned antelopes. The evolutionary relationship betwee ...
and human
lactoferrin Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, su ...
s were found to be potent inhibitors of EV71 infection" and "
ribavirin Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pegin ...
could be a potential anti-EV71 drug."


Research

A joint UK and Chinese team working at the UK's national synchrotron facility near
Oxford Oxford () is a city in England. It is the county town and only city of Oxfordshire. In 2020, its population was estimated at 151,584. It is north-west of London, south-east of Birmingham and north-east of Bristol. The city is home to the ...
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.


Outbreaks


Australia

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.


Cambodia

From April through July 2012, at least 64 children died and two survived from a disease affecting children under 7 years old in
Cambodia Cambodia (; also Kampuchea ; km, កម្ពុជា, UNGEGN: ), officially the Kingdom of Cambodia, is a country located in the southern portion of the Indochinese Peninsula in Southeast Asia, spanning an area of , bordered by Thailand t ...
. 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 The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
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 Dengue fever is a mosquito-borne tropical disease caused by the dengue virus. Symptoms typically begin three to fourteen days after infection. These may include a high fever, headache, vomiting, muscle and joint pains, and a characterist ...
, and ''
Streptococcus suis ''Streptococcus suis'' is a peanut-shaped, Gram-positive bacterium, and an important pathogen of pigs. Endemic in nearly all countries with an extensive pig industry, ''S. suis'' is also a zoonotic disease, capable of transmission to humans from ...
''. and the use of
steroids A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
in the treatment of the infections.


China

HFMD was recognized in China in the 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 Hand, foot, and mouth disease (HFMD) is a common infection caused by a group of enteroviruses. It typically begins with a fever and feeling generally unwell. This is followed a day or two later by flat discolored spots or bumps that may blis ...
in
Shenzhen Shenzhen (; ; ; ), also historically known as Sham Chun, is a major sub-provincial city and one of the special economic zones of China. The city is located on the east bank of the Pearl River estuary on the central coast of southern province ...
,
People's Republic of China China, officially the People's Republic of China (PRC), is a country in East Asia. It is the world's most populous country, with a population exceeding 1.4 billion, slightly ahead of India. China spans the equivalent of five time zones and ...
, 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 Hand, foot, and mouth disease (HFMD) is a common infection caused by a group of enteroviruses. It typically begins with a fever and feeling generally unwell. This is followed a day or two later by flat discolored spots or bumps that may blis ...
in
Shenzhen Shenzhen (; ; ; ), also historically known as Sham Chun, is a major sub-provincial city and one of the special economic zones of China. The city is located on the east bank of the Pearl River estuary on the central coast of southern province ...
during this time.1 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 } Beijing ( ; ; ), alternatively romanized as Peking ( ), is the capital of the People's Republic of China. It is the center of power and development of the country. Beijing is the world's most populous national capital city, with over 21 ...
,
Chongqing Chongqing ( or ; ; Sichuanese dialects, Sichuanese pronunciation: , Standard Mandarin pronunciation: ), Postal Romanization, alternately romanized as Chungking (), is a Direct-administered municipalities of China, municipality in Southwes ...
, and
Jinan Jinan (), Postal Map Romanization, alternately romanization of Chinese, romanized as Tsinan, is the Capital (political), capital of Shandong province in East China, Eastern China. With a population of 9.2 million, it is the second-largest city i ...
. 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 Taiwan, officially the Republic of China (ROC), is a country in East Asia, at the junction of the East and South China Seas in the northwestern Pacific Ocean, with the People's Republic of China (PRC) to the northwest, Japan to the nort ...
. 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 Zhejiang ( or , ; , also romanized as Chekiang) is an eastern, coastal province of the People's Republic of China. Its capital and largest city is Hangzhou, and other notable cities include Ningbo and Wenzhou. Zhejiang is bordered by Jiang ...
, 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 Anhui , (; formerly romanized as Anhwei) is a landlocked province of the People's Republic of China, part of the East China region. Its provincial capital and largest city is Hefei. The province is located across the basins of the Yangtze River ...
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 Xinhua News Agency (English pronunciation: )J. C. Wells: Longman Pronunciation Dictionary, 3rd ed., for both British and American English, or New China News Agency, is the official state news agency of the People's Republic of China. Xinhua ...
reported the number of people infected also rose from 4,000 to 15,799.


Taiwan

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 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. 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 number 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

Vietnam recorded 63,780 cases of hand, foot and mouth disease in the first seven months of 2012. According to Tran Minh Dien, vice director of the National Hospital for Children, about 58.7% percent were caused by EV71.


See also

*
Enterovirus 68 Enterovirus D68 (EV-D68) is a member of the ''Picornaviridae'' family, an enterovirus. First isolated in California in 1962 and once considered rare, it has been on a worldwide upswing in the 21st century. It is suspected of causing a polio-like ...
, a similar, related virus also first isolated in California in the 1960s *
Herpangina Herpangina, also called mouth blisters, is a painful mouth infection caused by coxsackieviruses. Usually, herpangina is produced by one particular strain of coxsackie virus A (and the term "herpangina virus" refers to coxsackievirus A), but it can ...
, mouth blisters that can be caused by enteroviruses


References

{{DEFAULTSORT:Ev-71 Enteroviruses Infraspecific virus taxa