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Enterovirus 71 (EV71) (genus Enterovirus, family Picornaviridae), a common cause of hand, foot, and mouth disease (HFMD), may also cause severe neurological diseases, such as encephalitis and poliomyelitis-like paralysis. To examine the genetic diversity and rate of evolution of EV71, we have determined and analyzed complete VP1 sequences (891 nucleotides) for 113 EV71 strains isolated in the United States and five other countries from 1970 to 1998. Nucleotide sequence comparisons demonstrated three distinct EV71 genotypes, designated A, B, and C. The genetic variation within genotypes (12% or fewer nucleotide differences) was less than the variation between genotypes (16.5 to 19.7%). Strains of all three genotypes were at least 94% identical to one another in deduced amino acid sequence. The EV71 prototype strain, BrCr-CA-70, isolated in California in 1970, is the sole member of genotype A. Strains isolated in the United States and Australia during the period from 1972 to 1988, a 1994 Colombian isolate, and isolates from a large HFMD outbreak in Malaysia in 1997 are all members of genotype B. Although strains of genotype B continue to circulate in other parts of the world, none have been isolated in the United States since 1988. Genotype C contains strains isolated in 1985 or later in the United States, Canada, Australia, and the Republic of China. The annual rate of evolution within both the B and C genotypes was estimated to be approximately 1.35 x 10(-2) substitutions per nucleotide and is similar to the rate observed for poliovirus. The results indicate that EV71 is a genetically diverse, rapidly evolving virus. Its worldwide circulation and potential to cause severe disease underscore the need for additional surveillance and improved methods to identify EV71 in human disease.

Between November 1972 and May 1973, 60 strains of a new enterovirus were isolated from 49 patients investigated at Fairfield Hospital for Communicable Diseases, Melbourne. Of these patients 39 were admitted to hospital with aseptic meningitis (which was accompanied by a rash in 6), 5 others had rash alone, 4 had acute respiratory tract infections, and 1 had infective polyneuritis. A representative strain from this outbreak had the physicochemical properties of an enterovirus but could not be identified with antisera prepared against the prototype polio, coxsackie, and echo viruses. Studies, performed in association with the WHO Collaborating Centre for Virus Reference and Research, Houston, TX, USA, showed the outbreak to be due to enterovirus 71. Most of the epidemic strains required sodium deoxycholate treatment before neutralization could be demonstrated.

An outbreak of infections caused by enterovirus 71 occurred in southeastern Australia during the winter of 1986. Infection was confirmed by virus isolation or serology in 114 patients, 65 of whom were admitted to hospital. Fifty-one percent of inpatients were infants younger than 12 months old and 85% were younger than 5 years old. Many cases of hand, foot and mouth disease occurred in the community during the epidemic, but 51% (33 of 65) of patients admitted to hospital had central nervous system involvement, often associated with severe symptoms. Six patients had encephalitis and one had a poliomyelitis-like paralytic illness. Various skin manifestations other than hand, foot and mouth disease occurred, especially in young children, and 25 patients had significant respiratory disease including at least 7 with pneumonia. Enterovirus 71 is one of very few viruses that cause hand, foot and mouth disease as well as a variety of other clinical manifestations. The most important of these is meningoencephalitis, which causes significant morbidity, especially in infants and young children.