Enteroviruses alone, excluding the poliovirus, cause about 10 to 15 million infections in the United States each year. Tens of thousands of individuals are hospitalized each year for illnesses caused by enteroviruses. Enterovirus D68 (EV-D68, EV68, HEV68) is a member of the Picornaviridae family, an enterovirus. First isolated in California in 1962 and once considered rare, EV-D68 has been on a worldwide upswing in the 21st century.1
In 2014, the United States experienced a nationwide outbreak of EV-D68 associated with severe respiratory illness. From mid-August 2014 to January 15, 2015, the CDC or state public health laboratories confirmed 1,153 total cases of respiratory illness caused by EV-D68 in 49 states and the District of Columbia.1 Almost all of the confirmed cases were among children, many of whom had asthma or a history of wheezing.
Additionally, there were likely millions of mild EV-D68 infections for which individuals did not seek medical treatment and get tested.2
The CDC received about 2,600 specimens for enterovirus laboratory testing during 2014, which is substantially more than usual. About 36% of those tested positive for EV-D68. About 33% tested positive for an enterovirus or rhinovirus other than EV-D68. EV-D68 was detected in specimens from 14 patients who died and had samples submitted for testing. State and local officials have the authority to determine and release information about the cause of these deaths.1
The pain and suffering caused by the enteroviruses and the upsurge specifically in EV-D68 infections have caused the world to pause, back up and investigate retrospectively why there has been an upsurge in activity and how better can we as healthcare providers prevent EV-D68 infections in the future before EV-D68 raises its ugly head again.
Enteroviruses affect millions of people worldwide each year. They are often found in the respiratory secretions (e.g., saliva, sputum, or nasal mucus) and stool of an infected individual. Historically, poliomyelitis was the most significant disease caused by an enterovirus, i.e., the poliovirus.
There are 64 non-polio enteroviruses that can cause disease in humans: 23 Coxsackie A viruses, 6 Coxsackie B viruses, 28 echoviruses, and five 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, i.e., the common cold, hand, foot and mouth disease, acute hemorrhagic conjunctivitis, aseptic meningitis, myocarditis, severe neonatal sepsis-like disease, and acute flaccid myelitis.
Enteroviruses are members of the Picornaviridae family (Table 1), a large and diverse group of small RNA viruses characterized by a positive-sense single-stranded RNA (ssRNA) associated with several human and mammalian diseases. 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.
Serologic studies have distinguished 71 human enterovirus serotypes based on antibody neutralization tests. Additional antigenic variants have been defined within several of the serotypes based on reduced or nonreciprocal cross-neutralization between variant strains.
Based on their pathogenesis in humans and animals, the enteroviruses were initially classified into four groups: Polioviruses, Coxsackie A viruses (CA), Coxsackie B viruses (CB), and Echoviruses. 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 species designation and consecutive numbers: EV-D68, EV-B69, EV-D70, EV-A71, etc.
Table 1: ENTEROVIRUSES3
| Group: || Group IV ((+)ssRNA) |
| Order: ||Picornavirales|
| Family: || Picornaviridae |
| Species ||Enterovirus A Enterovirus B Enterovirus C Enterovirus D Enterovirus E Enterovirus F Enterovirus G Enterovirus H Enterovirus J Rhinovirus A Rhinovirus B Rhinovirus C |
The enterovirus genus includes the following twelve species3:
- Enterovirus A (formerly Human enterovirus A)
- Enterovirus B (formerly Human enterovirus B)
- Enterovirus C (formerly Human enterovirus C)
- Enterovirus D (formerly Human enterovirus D)
- Enterovirus E (formerly Bovine enterovirus group A)
- Enterovirus F (formerly Bovine enterovirus group B)
- Enterovirus G (formerly Porcine enterovirus B)
- Enterovirus H (formerly Simian enterovirus A)
- Enterovirus J
- Rhinovirus A (formerly Human rhinovirus A)
- Rhinovirus B (formerly Human rhinovirus B)
- Rhinovirus C (formerly Human rhinovirus C)
Within these twelve species are the serotypes:
- Coxsackieviruses are a non-phylogenetic group. Coxsackie A viruses (CV-A) tend to infect the skin and mucous membranes, causing herpangina, acute hemorrhagic conjunctivitis, and hand, foot, and mouth (HFM) disease. Coxsackie B viruses (CV-B) tend to infect the heart, pleura, pancreas, and liver causing pleurodynia, myocarditis, pericarditis, hepatitis, and pancreatitis. Both Coxsackie A and B can cause nonspecific febrile illnesses, rashes, upper respiratory tract disease, and aseptic meningitis.
- Serotypes CV-A1, CV-A11, CV-A13, CV-A17, CV-A19, CV-A20, CV-A21, CV-A22, and CV-A24 (found under the species: Enterovirus C).
- Serotypes CV-B1, CV-B2, CV-B3, CV-B4, CV-B5, CV-B6, and CV-A9 (found under the species: Enterovirus B).
- Serotypes CV-A2, CV-A3, CV-A4, CV-A5, CV-A6, CV-A7, CV-A8, CV-A10, CV-A12, CV-A14 and CV-A16 (found under the species: Enterovirus A).
- Echovirus (E)
- Echoviruses are a cause of many of the nonspecific viral infections. It is highly infectious, and its primary target is children. The echovirus is among the leading causes of acute febrile illness in infants and young children and is the most common cause of aseptic meningitis. Infection of an infant with this virus following birth may cause severe systemic diseases and is associated with high infant mortality rates. Echoviruses are found in the gastrointestinal tract and can cause nervous disorders. The usual symptoms of echoviruses are fever, mild rash, and mild upper respiratory tract (URT) illness.
- serotypes E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-9, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20, E-21, E-24, E-25, E-26, E-27, E-29, E-30, E-31, E-32, and E-33 (found under the species: Enterovirus B).
- Enterovirus (EV)
- Serotypes EV-A71, EV-A76, EV-A89, EV-A90, EV-A91, EV-A92, EV-A114, EV-A119, SV19, SV43, SV46 and BA13 (found under the species: Enterovirus A).
- Serotypes EV-B69, EV-B73, EV-B74, EV-B75, EV-B77, EV-B78, EV-B79, EV-B80, EV-B81, EV-B82, EV-B83, EV-B84, EV-B85, EV-B86, EV-B87, EV-B88, EV-B93, EV-B97, EV-B98, EV-B100, EV-B101, EV-B106, EV-B107, EV-B110 and SA5 (found under the species: Enterovirus B).
- Serotypes EV-C95, EV-C96, EV-C99, EV-C102, EV-C104, EV-C105, EV-C109, EV-C116, EV-C117 and EV-C118 (found under the species: Enterovirus C).
- Serotypes EV-D68, EV-D70, EV-D94, EV-D111, and EV-D120 (found under the species: Enterovirus D).
- Serotypes EV-H1 (found under the species: Enterovirus H).
- Serotypes SV6, EV-J103, EV-J108, EV-J112, EV-J115, and EV-J121 (found under the species: Enterovirus J).
- Human rhinovirus (HRV)
- 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.
- Serotypes HRV-A1, HRV-A2, HRV-A7, HRV-A8, HRV-A9, HRV-A10, HRV-A11, HRV-A12, HRV-A13, HRV-A15, HRV-A16, HRV-A18, HRV-A19, HRV-A20, HRV-A21, HRV-A22, HRV-A23, HRV-A24, HRV-A25, HRV-A28, HRV-A29, HRV-A30, HRV-A31, HRV-A32, HRV-A33, HRV-A34, HRV-A36, HRV-A38, HRV-A39, HRV-A40, HRV-A41, HRV-A43, HRV-A44, HRV-A45, HRV-A46, HRV-A47, HRV-A49, HRV-A50, HRV-A51, HRV-A53, HRV-A54, HRV-A55, HRV-A56, HRV-A57, HRV-A58, HRV-A59, HRV-A60, HRV-A61, HRV-A62, HRV-A63, HRV-A64, HRV-A65, HRV-A66, HRV-A67, HRV-A68, HRV-A71, HRV-A73, HRV-A74, HRV-A75, HRV-A76, HRV-A77, HRV-A78, HRV-A80, HRV-A81, HRV-A82, HRV-A85, HRV-A88, HRV-A89, HRV-A90, HRV-A94, HRV-A95, HRV-A96, HRV-A98, HRV-A100, HRV-A101, HRV-A102 and HRV-A103 (found under the species: Rhinovirus A).
- serotypes HRV-B3, HRV-B4, HRV-B5, HRV-B6, HRV-B14, HRV-B17, HRV-B26, HRV-B27, HRV-B35, HRV-B37, HRV-B42, HRV-B48, HRV-B52, HRV-B69, HRV-B70, HRV-B72, HRV-B79, HRV-B83, HRV-B84, HRV-B86, HRV-B91, HRV-B92, HRV-B93, HRV-B97, and HRV-B99 (found under the species: Rhinovirus B).
- serotypes HRV-C1, HRV-C2, HRV-C3, HRV-C4, HRV-C5, HRV-C6, HRV-C7, HRV-C8, HRV-C9, HRV-C10, HRV-C11, HRV-C12, HRV-C13, HRV-C14, HRV-C15, HRV-C16, HRV-C17, HRV-C18, HRV-C19, HRV-C20, HRV-C21, HRV-C22, HRV-C23, HRV-C24, HRV-C25, HRV-C26, HRV-C27, HRV-C28, HRV-C29, HRV-C30, HRV-C31, HRV-C32, HRV-C33, HRV-C34, HRV-C35, HRV-C36, HRV-C37, HRV-C38, HRV-C39, HRV-C40, HRV-C41, HRV-C42, HRV-C43, HRV-C44, HRV-C45, HRV-C46, HRV-C47, HRV-C48, HRV-C49, HRV-C50 and HRV-C51 (found under the species: Rhinovirus C.)
- Poliovirus (PV)
- There are three serotypes of poliovirus, PV1, PV2, and PV3. Each has 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.
- Serotypes PV-1, PV-2, & PV-3 found under the species: Enterovirus C.