Enterovirus

# Overview
Enteroviruses are a genus of (+)ssRNA viruses associated with several human and mammalian diseases. Serologic studies have distinguished 66 human enterovirus serotypes on the basis of antibody neutralization tests. Additional antigenic variants have been defined within several of the serotypes on the basis of reduced or nonreciprocal cross-neutralization between variant strains. On the basis of their pathogenesis in humans and animals, the enteroviruses were originally classified into four groups, polioviruses, Coxsackie A viruses (CA), Coxsackie B viruses (CB), and echoviruses, but it was quickly realized that there were significant overlaps in the biological properties of viruses in the different groups. Enteroviruses isolated more recently are named with a system of consecutive numbers: EV68, EV69, EV70, and EV71, etc.
Enteroviruses affect millions of people worldwide each year, and are often found in the respiratory secretions (e.g., saliva, sputum, or nasal mucus) and stool of an infected person. Historically, poliomyelitis was the most significant disease caused by an enterovirus, Poliovirus. There are 62 non-polio enteroviruses that can cause disease in humans: 23 Coxsackie A viruses, 6 Coxsackie B viruses, 28 echoviruses, and 5 other enteroviruses. Poliovirus, as well as coxsackie and echovirus are spread through the fecal-oral route. Infection can result in a wide variety of symptoms ranging from mild respiratory illness (common cold), hand, foot and mouth disease, acute hemorrhagic conjunctivitis, aseptic meningitis, myocarditis, severe neonatal sepsis-like disease, and acute flaccid paralysis.

# Species and genetics
Enteroviruses are members of the picornavirus family, a large and diverse group of small RNA viruses characterized by a single positive-strand genomic RNA. All enteroviruses contain a genome of approximately 7,500 bases and are known to have a high mutation rate due to low-fidelity replication and frequent recombination. After infection of the host cell, the genome is translated in a cap-independent manner into a single polyprotein, which is subsequently processed by virus-encoded proteases into the structural capsid proteins and the nonstructural proteins, which are mainly involved in the replication of the virus.
The enterovirus genus includes the following ten species:
- Bovine enterovirus
- Human enterovirus A
- Human enterovirus B
- Human enterovirus C
- Human enterovirus D
- Human rhinovirus A
- Human rhinovirus B
- Human rhinovirus C
- Porcine enterovirus B
- Simian enterovirus A
Within these ten species are the serotypes:
- Coxsackievirus
serotypes CV-A2, CV-A3, CV-A4, CV-A5, CV-A6, CV-A7, CV-A8, CV-A10, CV-A12, CV-A14, & CV-A16 found under the species: Human enterovirus A.
serotypes CV-B1, CV-B2, CV-B3, CV-B4, CV-B5, CV-B6, CV-A9, & CV-A23 found under the species: Human enterovirus B.
serotypes CV-A1, CV-A11, CV-A13, CV-A17, CV-A19, CV-A20, CV-A21, CV-A22, & CV-A24 found under the species: Human enterovirus C.
- Echovirus
serotypes E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-19, E20, E-21, E-24, E-25,                  E-26, E-27, E-29, E-30, E-31, E-32, & E-33 found under the species: Human enterovirus B.
- Enterovirus
serotypes EV-71, EV-76, EV-89, EV-90, EV-91, & EV-92 found under the species: Human enterovirus A.
serotypes EV-69, EV-73, EV-74, EV-75, EV-77, EV-78, EV-79, EV-80, EV-81, EV-82, EV-83, EV-84, EV-85, EV-86, EV-87, EV-88,                  EV-93, EV-97, EV-98, EV-100, EV-101, EV-106, & EV-107 found under the species: Human enterovirus B.
serotypes EV-95, EV-96, EV-99, EV-102, EV-104, EV-105, & EV-109 found under the species: Human enterovirus C.
serotypes EV-68, EV-70, & EV-94 found under the species: Human enterovirus D.

# Treatment

## Antimicrobial therapy
- Enterovirus D68 treatment
- Preferred regimen: supportive therapy
- Note: A new drug Pleconaril designed to affect Rhinovirus is being suggested to be effective against Enterovirus D68 but further investigation is required
- Human rhinovirus
serotypes HRV-1, HRV-2, HRV-7, HRV-8, HRV-9, HRV-10, HRV-11, HRV-12, HRV-13, HRV-15, HRV-16, HRV-18, HRV-19, HRV-20,                  HRV-21, HRV-22, HRV-23, HRV-24, HRV-25, HRV-28, HRV-29, HRV-30, HRV-31, HRV-32, HRV-33, HRV-34, HRV-36,                  HRV-38, HRV-39, HRV-40, HRV-41, HRV-43, HRV-44, HRV-45, HRV-46, HRV-47, HRV-49, HRV-50, HRV-51, HRV-53,                  HRV-54, HRV-55, HRV-56, HRV-57, HRV-58, HRV-59, HRV-60, HRV-61, HRV-62, HRV-63, HRV-64, HRV-65, HRV-66,                  HRV-67, HRV-68, HRV-71, HRV-73, HRV-74, HRV-75, HRV-76, HRV-77, HRV-78, HRV-80, HRV-81, HRV-82, HRV-85,                  HRV-88, HRV-89, HRV-90, HRV-94, HRV-95, HRV-96, HRV-98, & HRV-100 found under the species: Human rhinovirus A.
serotypes HRV-3, HRV-4, HRV-5, HRV-6, HRV-14, HRV-17, HRV-26, HRV-27, HRV-35, HRV-37, HRV-42, HRV-48, HRV-52, HRV-69, HRV-70,                  HRV-72, HRV-79, HRV-83, HRV-84, HRV-86, HRV-91, HRV-92, HRV-93, HRV-97, & HRV-99 found under the species: Human rhinovirus B.
- Poliovirus
serotypes PV-1, PV-2, & PV-3 found under the species: Human enterovirus C.

## Coxsackie and echovirus
Coxsackie viruses are a non-phylogenetic group. Coxsackie A viruses are mainly associated with human hand, foot and mouth disease. Coxsackie B viruses can cause mild signs and symptoms, similar to a "cold", but these viruses also can lead to more serious diseases, including myocarditis (inflammation of the heart); pericarditis (inflammation of the sac lining the heart); meningitis (inflammation of the membranes that line the brain and spinal cord); and pancreatitis (inflammation of the pancreas).
Echoviruses are a cause of many of the nonspecific viral infections. It is mainly found in the intestine, and can cause nervous disorders. The usual symptoms of Coxsackie and echovirus are fever, mild rash, and mild upper respiratory tract (URT) illness.

## Enterovirus 71
Enterovirus 71 (EV-71) is notable as one of the major causative agents for hand, foot and mouth disease (HFMD), and is sometimes associated with severe central nervous system diseases. EV71 was first isolated and characterized from cases of neurological disease in California in 1969. To date, little is known about the molecular mechanisms of host response to EV71 infection, but increases in the level of mRNAs encoding chemokines, proteins involved in protein degradation, complement proteins, and proapoptotis proteins have been implicated.

## Poliovirus
There are three serotypes of poliovirus, PV1, PV2, and PV3; each with a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity.  PV1 is the most common form encountered in nature; however, all three forms are extremely infectious. Poliovirus can affect the spinal cord and cause poliomyelitis.
Polioviruses were formerly classified as a species belonging to the genus Enterovirus in the family Picornaviridae.  The Poliovirus species has been eliminated from the genus Enterovirus.  The following serotypes, Human poliovirus 1, Human poliovirus 2, and Human poliovirus 3, were assigned to the species Human enterovirus C, in the genus Enterovirus in the family Picornaviridae.  The type species of the genus Enterovirus was changed from Poliovirus to Human enterovirus C.  This has been ratified in April 2008.
The 39th Executive Committee (EC39) of the International Committee on Taxonomy of Viruses (ICTV) met in Canada during June 2007 with new taxonomic proposals.
Two of the proposals with three changes were:
- Code 2005.261V.04: To remove the following species Poliovirus from the existing genus Enterovirus in the family Picornaviridae.
- Code 2005.262V.04: To assign the viruses; PV-1, PV-2, PV-3 to the existing species Human enterovirus C in the genus Enterovirus in the family Picornaviridae.
- Code 2005.263V.04: To change the type species Poliovirus from the existing genus Enterovirus in the family Picornaviridae to the type species Human enterovirus C.
Proposals approved at the (EC39) meeting of 2007, were sent to members of ICTV via email for ratification and have become official taxonomy.  There have been a total of 215 taxonomic proposals, which have been approved and ratified since the 8th ICTV Report of 2005.
The ratification process was performed by email.  The proposals were sent electronically via email on March 18, 2008 to ICTV members with a request to vote on whether to ratify the taxonomic proposals, with a 1-month deadline.
The following are two of the taxonomic proposals with three changes that were ratified by ICTV members in April 2008:
Picornaviruses
- 2005.261V.04: To remove the following species from the existing genus Enterovirus in the family Picornaviridae: Poliovirus.(Note: Poliovirus hereby loses its status as a virus species).
- 2005.262V.04: To assign the following viruses to the species Human enterovirus C in the existing genus Enterovirus in the family Picornaviridae: Human poliovirus 1, Human poliovirus 2, Human poliovirus 3. (This is not strictly necessary as a taxonomic proposal because it concerns entities below the species level, but it is left in to clarify this reorganization of the Picornaviridae).
- 2005.263V.04: To change the type species of the genus Enterovirus in the family Picornaviridae, from Poliovirus to Human enterovirus C.
The ICTVdb, International Committee on Taxonomy of Viruses data base, based on the ICTV Master Species List, 8th Report, June 2005 is obsolete.

## Rhinovirus
There are three species of Rhinoviruses: Human Rhinovirus A, Human Rhinovirus B, and Human Rhinovirus C which contain over 100 serotypes.  Rhinoviruses are the most suspected causative agents of the common cold.  This makes it difficult to develop a single vaccine against so many serotypes.

# Treatment

## Antimicrobial therapy
- Rhinovirus treatment (commom cold)
- Supportive therapy
- Symptomatic treatment-Ipratropium bromide intranasal (2 sprays tid) AND Clemastine 1.34 mg 12 tab PO bidtid (over the counter)
- Symptomatic relief by Ipratropium nasal spray decreases rhinorrhea and sneezing vs placebo. AND Clemastine (an antihistamine) decreases sneezing, rhinorrhea but associated with dry nose, mouth & throat in 619%.OR Oral pleconaril given within 24 hrs of onset reduced duration (1 day) & severity of cold symptoms in DBPCT (p < .001).
- Note (1): No antiviral treatment indicated.

# Diseases caused by enterovirus infection
- Poliomyelitis is the most notable disease caused by enterovirus infection.
- Nonspecific febrile illness is the most common presentation of enterovirus infection. Other than fever, symptoms include muscle pain, sore throat, gastrointestinal distress, and headache. Abdominal discomfort may also be reported in some patients.
- Enteroviruses are by far the most common causes of aseptic meningitis in children. In the United States, enteroviruses are responsible for 30,000 to 50,000 meningitis hospitalizations per year as a result of 30 million to 50 million infections.
- Pleurodynia is characerized by severe paroxysmal pain in the chest and abdomen, along with fever, and sometimes nausea, headache, and emesis.
- Pericarditis and/or myocarditis are typically caused by enteroviruses; symptoms consist of fever with dyspnea and chest pain. Arrhythmias, heart failure, and myocardial infarction have also been reported.
- Acute hemorrhagic conjunctivitis can be caused by enteroviruses.
- Herpangina is caused by Coxsackie A virus, and causes a vesicular rash in the oral cavity and on the pharynx, along with  high fever, sore throat, malaise, and often dysphagia, loss of appetite, back pain, and headache. It is also self limiting, with symptoms typically ending in 34 days.
- Hand, foot and mouth disease is a childhood illness most commonly caused by infection by Coxsackie A virus or EV71.
- Encephalitis is rare manifestation of enterovirus infection; when it occurs, the most frequent enterovirus found to be causing it is echovirus 9.
- Bornholm disease is enteroviral in origin.
- A 2007 study suggested that acute respiratory or gastrointestinal infections associated with enterovirus may be a factor in chronic fatigue syndrome.

## Treatment
Treatment for enteroviral infection is mainly supportive. In cases of pleurodynia, treatment consists of analgesics to relieve the severe pain that occurs in patients with the disease; in some severe cases, opiates may be needed. Treatment for aseptic meningitis caused by enteroviruses is also mainly symptomatic. In patients with enteroviral carditis, treatment consists of the prevention and treatment of complications, such as arrhythmias, pericardial effusion, and cardiac failure. Other treatments that have been investigated for enteroviral carditis include intravenous immunoglobulin.

# Gallery
- Electron micrograph of the poliovirus, a species of Enterovirus. From Public Health Image Library (PHIL). 
- Girl with skin lesions on the face due to echovirus type 9. From Public Health Image Library (PHIL). 
- Child displays a deformity of her right lower extremity due to polio caused by the poliovirus, an enterovirus member. From Public Health Image Library (PHIL). 
Child displays a deformity of her right lower extremity due to polio caused by the poliovirus, an enterovirus member. From Public Health Image Library (PHIL). 
- Immunoelectron microscopic technique able to discern the morphologic traits of the Coxsackie B4 virus virions. From Public Health Image Library (PHIL). 
- Immunoelectron microscopic technique able to discern the morphologic traits of the Coxsackie B4 virus virions. From Public Health Image Library (PHIL). 
- Transmission electron micrograph (TEM) reveals the presence of coxsackie B3 virus particles,  found within a specimen of muscle tissue. From Public Health Image Library (PHIL). 
- Transmission electron micrograph (TEM) depicts a number of virions found responsible for a case of acute hemorrhagic conjunctivitis (AHC). From Public Health Image Library (PHIL). 
- ransmission electron micrograph (TEM) depicts a number of virions found responsible for a case of acute hemorrhagic conjunctivitis (AHC).From Public Health Image Library (PHIL). 
- Transmission electron micrograph (TEM) reveals numerous, spheroid-shaped Enterovirus-D68 (EV-D68) virions. From Public Health Image Library (PHIL). 
- Transmission electron micrograph (TEM) reveals numerous, spheroid-shaped Enterovirus-D68 (EV-D68) virions. From Public Health Image Library (PHIL).