Enteroviruses An Overview

Enteroviruses Enteroviruses are a genus of the picornavirus family which replicate mainly in the gut. Single stranded naked RNA virus with icosahedral symmetry Unlike rhinoviruses, they are stable in acid pH Capsid has 60 copies each of 4 proteins, VP1, VP2, VP3 and VP4 arranged with icosahedral symmetry around a positive sense genome. At least 71 serotypes are known: divided into 5 groups Polioviruses Coxsackie A viruses Coxsackie B viruses Echoviruses Enteroviruses (more recently, new enteroviruses subtype have been allocated sequential numbers (68-71))

Enterovirus Particles Courtesy of Linda M. Stannard, University of Cape Town, S.A.h

History Poliovirus - first identified in 1909 by inoculation of specimens into monkeys. The virus was first grown in cell culture in 1949 which became the basis for vaccines. Coxsackieviruses - In 1948, a new group of agents were identified by inoculation into newborn mice from two children with paralytic disease. These agents were named coxsackieviruses after the town in New York State. Coxsackieviruses A and B were identified on the basis of the histopathological changes they produced in Newborn mice and their capacity to grow in cell cultures. Echoviruses - were later identified which produced cytopathic changes in cell culture and was nonpathogenic for newborn mice and subhuman primates. More recently, new enterovirus types have been allocated sequential numbers (68 - 71).

Properties of Enteroviruses

Poliovirus 3 serotypes of poliovirus (1, 2, and3) but no common antigen. Have identical physical properties but only share 36-52% nucleotide homology. Humans are the only susceptible hosts. Polioviruses are distributed globally. Before the availability of immunization, almost 100% of the population in developing countries before the age of 5. The availability of immunization and the poliovirus eradication campaign has eradicated poliovirus in most regions of the world except in the Indian Subcontinent and Africa. Poliovirus is on course of being eradicated worldwide by the end of 2000 or 2001.

Pathogenesis The incubation period is usually 7 - 14 days. Following ingestion, the virus multiplies in the oropharyngeal and intestinal mucosa. The lymphatic system, in particular the tonsils and the Peyer's patches of the ileum are invaded and the virus enters the blood resulting in a transient viraemia. In a minority of cases,the virus may involve the CNS following dissemination.

Clinical Manifestations There are 3 possible outcomes of infection: Subclinical infection (90 - 95%) - inapparent subclinical infection account for the vast majority of poliovirus infections. Abortive infection (4 - 8%) - a minor influenza-like illness occurs, recovery occurs within a few days and the diagnosis can only be made by the laboratory. The minor illness may be accompanied by aseptic meningitis Major illness (1 - 2%) - the major illness may present 2 - 3 days following the minor illness or without any preceding minor illness. Signs of aseptic meningitis are common. Involvement of the anterior horn cells lead to flaccid paralysis. Involvement of the medulla may lead to respiratory paralysis and death.

Laboratory Diagnosis Virus Isolation Serology Mainstay of diagnosis of poliovirus infection poliovirus can be readily isolated from throat swabs, faeces, and rectal swabs. It is rarely isolated from the CSF Can be readily grown and identified in cell culture Requires molecular techniques to differentiate between the wild type and the vaccine type. Serology Very rarely used for diagnosis since cell culture is efficient. Occasionally used for immune status screening for immunocompromised individuals.

Prevention (1) No specific antiviral therapy is available. However the disease may be prevented through vaccination. There are two vaccines available. Intramuscular Poliovirus Vaccine (IPV) consists of formalin inactivated virus of all 3 poliovirus serotypes. Produces serum antibodies only: does not induce local immunity and thus will not prevent local infection of the gut. However, it will prevent paralytic poliomyelitis since viraemia is essential for the pathogenesis of the disease. Oral Poliovirus Vaccine (OPV) Consists of live attenuated virus of all 3 serotypes. Produces local immunity through the induction of an IgA response as well as systemic immunity. Rarely causes paralytic poliomyelitis, around 1 in 3 million doses.

Prevention (2) Most countries use OPV because of its ability to induce local immunity and also it is much cheaper to produce than IPV. The normal response rate to OPV is close to 100%. OPV is used for the WHO poliovirus eradication campaign. Because of the slight risk of paralytic poliomyelitis, some Scandinavian countries have reverted to using IPV. Because of the lack of local immunity, small community outbreaks of poliovirus infections have been reported. Poliovirus was targeted for eradication by the WHO by the end of year 2000 (now 2005). To this end, an extensive monitoring network had been set up. Poliovirus has been eradicated from most regions of the world except the Indian subcontinent and sub-Saharan Africa. It is possible that the WHO target may be achieved.

Current Status of Wild Poliovirus Transmission

Coxsackieviruses Coxsackieviruses are distinguished from other enteroviruses by their pathogenicity for suckling rather than adult mice. They are divided into 2 groups on the basis of the lesions observed in suckling mice. Group A viruses produce a diffuse myositis with acute inflammation and necrosis of fibers of voluntary muscles. Group B viruses produce focal areas of degeneration in the brain, necrosis in the skeletal muscles, and inflammatory changes in the dorsal fat pads, the pancreas and occasionally the myocardium. Each of the 23 group A and 6 group B coxsackieviruses have a type specific antigen. In addition, all from group B and one from group A (A9) share a group Ag. Cross-reactivities have also been demonstrated between several group A viruses but no common group antigen has been found.

Echoviruses The first echoviruses were accidentally discovered in human faeces, unassociated with human disease during epidemiological studies of polioviruses. The viruses were named echoviruses (enteric, cytopathic, human, orphan viruses). These viruses were produced CPE in cell cultures, but did not induce detectable pathological lesions in suckling mice. Altogether, There are 32 echoviruses (types 1-34; echovirus 10 and 28 were found to be other viruses and thus the numbers are unused) There is no group echovirus Ag but heterotypic cross-reactions occur between a few pairs.

New Enteroviruses Newly identified picornaviruses that are not polioviruses are no longer classified separated into the species coxsackie and echovirus because of the ambiguities presented by overlapping host range variations. 4 new enteroviruses have been identified (68 - 72). Enterovirus 70 is the causative agent epidemics of acute haemorrhagic conjunctivitis that swept through Africa, Asia, India and Europe from 1969 to 1974. The virus is occasionally neurovirulent. Enterovirus 71 appears to be highly pathogenic and has been associated with epidemics of a variety of acute diseases, including aseptic meningitis, encephalitis, paralytic poliomyelitis-like disease and hand-foot-mouth disease. Enterovirus 72 was originally assigned to hepatitis A virus, but it had now been assigned to a new family called heptoviruses.

Diseases associated with Enteroviruses

Disease Associations (1) Paralytic Disease - most commonly associated with polioviruses but other enteroviruses may also be responsible, notably enterovirus 71 Meningitis - caused by all groups of enteroviruses, most commonly seen in children under 5 years of age. Encephalitis - focal or generalized encephalitis may accompany meningitis. Most patients recover completely with no neurological deficit. Undifferentiated febrile illness - may be seen with all groups of enteroviruses. Hand foot mouth disease - usually caused by group A coxsackieviruses although group B coxsackieviruses and other enteroviruses have been caused outbreaks. Herpangina - caused by group A coxsackieviruses. Epidemic Pleurodynia (Bornholm disease) - normally caused by group B coxsackieviruses.

Disease Associations (2) Myocarditis - group B coxsackieviruses are the major cause of myocarditis, although it may be caused by other enteroviruses. It may present in neonates as part of neonatal infection and is often fatal. In adults, the disease is rarely fatal. Respiratory Infections - several enteroviruses are associated with the common cold. Rubelliform rashes - a rash disease resembling rubella may be seen with several coxsackie A, B, and echoviruses. Neonatal Infection - some coxsackie B viruses and echoviruses may cause infection in newborn infants. The virus is usually transmitted perinatally during the birth process and symptoms vary from a mild febrile illness to a severe fulminating multisystem disease and death. Conjunctivitis - associated with several types of enteroviruses, notably Coxsackie A24 and Enterovirus 70 (haemorrhagic conjunctivitis) Pancreatitis/Diabetes - associated with Coxsackie B virus infection. The extent of the role of the virus in diabetes is unknown.

Laboratory Diagnosis Virus Isolation Serology Mainstay of diagnosis of enterovirus infection Coxsackie B and Echoviruses can be readily grown in cell culture from throat swabs, faeces, and rectal swabs. They can also be isolated from the CSF Coxsackie A viruses cannot be easily isolated in cell culture. They can be isolated readily in suckling mice but this is not offered by most diagnostic laboratories because of practical considerations. Molecular techniques may provide a better alternative. Serology Very rarely used for diagnosis since cell culture is efficient. Neutralization tests or EIAs are used but are very cumbersome and thus not offered by most diagnostic laboratories

Cytopathic Effect (Virology Laboratory, New-Yale Haven Hospital)

Management and Prevention There is no specific antiviral therapy available against enteroviruses other than polio. Some authorities use IVIG in the treatment of neonatal infections or severe infections in immunocompromised individuals. However, the efficacy is uncertain. HNIG have been to prevent outbreaks of neonatal infection with good results. There is no vaccine available mainly because of the multiplicity of serotypes. There is little interest in developing a vaccine except against enterovirus 71 and coxsackie B viruses.