Infectious Diseases

Enteroviruses including poliovirus, echovirus, coxsackievirus

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Enteroviruses are a genera within the family Picornaviridae. They have a single strand RNA genome. Each capsid is comprised of 60 subunits, formed from four structural proteins (V1-V4) and is 27nm in size. The Enteroviruses are divided into 5 species (poliovirus and human enteroviruses A, B, C, D) based on homology of the genome that codes for the capsid V1 protein. The non-polio enteroviruses include reclassified as above include Group A and Group B coxsackieviruses, echoviruses and enteroviruses.

What is the best treatment?

  • Most enterovirus infections are self-limited and do not require treatment.

  • Poliovirus also is treated with supportive measures, including pain control and mechanical ventilation and intubation if needed.

  • For severe stomatitis, pain control and monitoring hydration and nutrition status is key, especially in young children

  • Clinicians may seek to provide treatment of serious enterovirus infections such as myocarditis and acute meningitis but there are no clinical studies to guide these strategies.

  • Both serum immune globulin and intravenous immune globulin (IVIG) have been used in children and adults with myocarditis or persistent meningoencephalitis, but there are no prospective data to evaluate these strategies, and available data about their effectiveness have been mixed.

  • There are some mixed data that an oral antiviral drug, pleconaril, may have some benefit in serious enteroviral infections, however this agent is not currently available or recommended for clinical use.

  • There are no significant issues with antiviral resistance.

How do patients contract this infection, and how do I prevent spread to other patients?

  • Epidemiology:

    • In temperate climates, enterovirus infections are highest in the summer and fall, however infections can occur year round.

    • However, the general pattern varies widely by specific virus. Some echoviruses are present year round, for example, while other serotypes (echovirus 9, 11, 70 and others) cause intermittent epidemics when there are enough susceptible individuals in a population.

    • Enteroviruses are largely transmitted by an oral fecal route, and infants are particularly high shedders in stool; direct contact may occur when changing diapers. Transmission can also occur through contaminated water and fomites.

    • Some enteroviruses can also be spread directly or via fomites by respiratory secretions and tears.

    • Poliovirus is spread via oral fecal transmission, or more rarely by pharyngeal spread. Ninety percent of infections are asymptomatic.

    • Enterovirus infections are highly prevalent worldwide.

    • Poliovirus, specifically, has been largely eradicated as a result of a worldwide concerted vaccination campaign. Incidence of acute flaccid paralysis due the virus decreased 99% between 1998 and 2003.

    • Endemic transmission has never been interrupted in Nigeria, India, Afghanistan and Pakistan, and has reoccurred in several countries including Sudan, Chad, Congo, Angola, Tajikistan, and Russia.

    • After sharp decreases in acute flaccid paralysis due to poliovirus, incidence is increasing again in certain countries due to incomplete vaccine coverage, migration and limited public health systems.

    • There have been some studies showing associations between enterovirus infections and type 1 diabetes, but there is no conclusive evidence that there is a causal pathway.

  • Infection control issues:

    • Contact precautions are important to decrease fecal-oral spread of enteroviruses, including poliovirus. Maintaining hygiene of the living environment and of water is also important.

    • Vaccination is the most effective way to prevent acute flaccid paralysis due to poliovirus.

    • There is no effective pre- or post-exposure viral prophylaxis.

What host factors protect against this infection?

  • An intact host antibody response is a protective factor against infection, in particular IgA in mucosal secretions.

  • Cell mediated immunity may actually increase inflammation and thus worsen clinical sequelae such as myocarditis without clearing the infection.

  • Newborns are susceptible to fulminant infections (especially with group B coxsackievirus serotypes 2-5 and echovirus 11), as are adults those with disorders of B lymphocyte function such as common variable immunodeficiency.

  • Individuals who are in contact with an infected individual are at high risk for infection. In particular, caretakers of infants who are changing diapers have a high likelihood of fecal oral contamination.

  • Infants less than one year of age have among the highest attack rates of infection overall.

  • Males have a greater risk of infection than females.

  • The pathogenesis of poliovirus has been best studied of the enteroviruses, in animal models. After initial virus ingestion, there is first a minor, then a major systemic viremia with symptoms in a minority of patients. This allows the virus to travel to and replicate in the CNS, leading to death of the motor neurons of the anterior horn of the spinal cord. It is not known whether this spread is hematogenous or via retrograde axonal transport. Brainstem neuron infection can also occur, leading to encephalitis.

What are the clinical manifestations of infection with this organism?

  • Poliomyelitis classically causes an acute flaccid paralysis as its most severe clinical manifestation.

  • Initial ingestion of virus leads to replication in the pharynx and small intestine.

  • There is then a ‘minor’ viremia which allows spread of virus to lymphoid tissue throughout the body, and then in less than 10% of individuals a ‘major’ viremia occurs with fever, malaise, fatigue, nausea, vomiting and CNS symptoms 8-12 days following exposure.

  • Asymmetric muscle weakness then ensues, the distribution depending on the extent of infection.

  • Legs are more commonly affected than arms, and proximal more often than distal muscles.

  • Reflexes are absent or diminished, but sensation is normal.

  • In some cases encephalitis or respiratory insufficiency can occur.

  • For the non-polio enteroviruses, symptoms may be nonspecific viral exanthems.

  • Group A coxsackieviruses cause hand, foot and mouth syndrome in children which causes fever, vesicles on the buccal mucosa and tongue, and tender skin lesions on the peripheral hands and feet especially. Symptoms generally resolve within a week without sequelae, but infected children may continue to shed virus in their stool for weeks.

  • Other cutaneous manifestations include purpuric or petechial rashes, and herpangina, vesicles of the tonsils and palate that is caused by coxsackie A viruses and primarily occur in children.

  • CNS manifestations (in addition to the acute flaccid paralysis of poliovirus detailed above) include aseptic meningitis and encephalitis. Enterovirus 71 can also rarely cause an acute flaccid paralysis similar to poliovirus, but is usually not permanent.

  • Other syndromes include myocarditis or pericarditis, and pleurodynia (an acute illness with pain of the chest wall and fever). These are all closely associated with group B coxsackieviruses

  • In the US in 2014, enterovirus D68 was a associated with a surge in respiratory infections in children, including severe disease. Many of the severely affected children had a history of asthma or wheezing.

What common complications are associated with infection with this pathogen?

  • In pregnant women without prior immunity, perinatal illness in late pregnancy with enteroviruses may rarely lead to fulminant neonatal infection in the postpartum period.

  • Rarely, vaccination with live oral polio vaccine (OPV) can lead to vaccine related poliomyelitis in the vaccinated individual or a contact (vaccine associated poliomyelitis). This occurs in only 1 in 2.5 million cases of vaccination. There have also been documented outbreaks of polio with strains found in the oral vaccine (vaccine-derived poliomyelitis). There is also an inactive polio vaccine (IPV) that is not associated with these side effects.

  • The complications of poliovirus infection are noted above. One additional complication is the post-polio syndrome in which weakness suddenly worsens many years or even decades after the initial illness. This can be accompanied by pain and general fatigue.

  • Management of post-polio syndrome is supportive, with pain control and a regular but non-strenuous exercise or physical therapy regimen.

  • In some children, enterovirus D68 has been associated with acute paralysis, similar to poliomyelitis.

How should I identify the organism?

  • Stool or rectal swabs are highest yield for enteroviruses. Throat swabs, serum or urine or cerebrospinal fluid (CSF) can also be used.

  • Viral cell culture is laborious, and requires inoculating several cell lines and looking for a cytopathic effect. The advantage of this method is that the isolate is available for further typing and characterization.

  • Polymerase chain reaction (PCR) is available and commonly used, especially for CSF specimens where it has increased sensitivity compared to cell culture. Other specimens that can be used are respiratory and serum. It is generally not possible to identify the enterovirus serotype using PCR, although specific testing for enterovirus D68 is available from the CDC.

  • Serology using type-specific immunoassays can be used on acute and convalescent sera (collected during the acute illness and then 3-4 weeks later). Since these are separate assays for each serotype, they may have limited utility in identifying the cause of acute illness.

  • The relative advantages and disadvantages of each method can be further discussed with a laboratorian or infectious diseases consultant.

How does this organism cause disease?

  • Enteroviruses have high levels of mutation on replication, which may contribute to evasion of immune control or clearance and also to development of neurotropism.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Non-polio enterovirus

Foster, CB, Friedman, N, Carl, J, Piedimonte, G. "Enterovirus D68: A clinically important respiratory enterovirus". Cleve Clin J Med. vol. 82. 2015 Jan. pp. 26-31.

(Provides an overview of the epidemiology and clinical features associated with the 2014 US outbreak.)

Ooi, MH, Wong, SC, Lewthwaite, P, Cardosa, MJ, Solomon, T. "Clinical features, diagnosis, and management of enterovirus 71". Lancet Neurol. vol. 9. 2010 Nov. pp. 1097-105.

(Good review of many aspects of enterovirus infections.)

Dennert, R, Crijns, HJ, Heymans, S. "Acute viral myocarditis". Eur Heart J. vol. 29. 2008 Sep. pp. 2073-82.

(Describes features of this condition.)

Poliomyelitis

Minor, PD. "The polio-eradication programme and issues of the end game". J Gen Virol. vol. 93. 2012 Mar. pp. 457-74.

(A summary of the logistical and ethical issues facing current polio eradication efforts worldwide.)
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