Enteroviruses

Updated: Feb 08, 2017
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Michael Stuart Bronze, MD  more...
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Overview

Practice Essentials

The human enteroviruses are ubiquitous viruses that are transmitted from person to person via direct contact with virus shed from the gastrointestinal or upper respiratory tract. Poliovirus, the prototypical enterovirus, can cause a subclinical or mild illness, aseptic meningitis, or paralytic poliomyelitis. The nonpolio viruses (group A and B coxsackieviruses, echoviruses, enteroviruses) are responsible for a wide spectrum of diseases in persons of all ages, although infection and illness occur most commonly in infants.

For updated epidemiologic information on the 2014 enterovirus 68 outbreak, see Frequency.

See 11 Travel Diseases to Consider Before and After the Trip, a Critical Images slideshow, to help identify and manage several infectious travel diseases.

Signs and symptoms

Clinical manifestations of enteroviral infection differ by viral type. Poliovirus syndromes can be abortive; nonparalytic; or paralytic, including spinal polio, bulbar polio, and polioencephalitis.

Polio

  • Abortive polio manifestations include fever, headache, sore throat, loss of appetite, vomiting, and abdominal pain; neurologic symptoms are typically not reported
  • Nonparalytic polio symptoms are similar to those of abortive polio but more intense; also, patients report stiffness of the posterior muscles of the neck, trunk, and limbs
  • Paralytic polio is an acute febrile illness characterized by aseptic meningitis and weakness or paralysis of one or more extremities, along with weakness of one or more muscle groups
  • Spinal polio comprises a prolonged prodrome, with features of aseptic meningitis followed in 1-2 days by weakness and, eventually, paralysis
  • Bulbar polio involves cranial nerves, most commonly IX, X, and XII; patients accumulate pharyngeal secretions, have a nasal twang to the voice, and develop paralysis of vocal cords, causing hoarseness, aphonia, and, eventually, asphyxia
  • Polioencephalitis is principally reported in children; unlike in other forms of polio, seizures are common and paralysis may be spastic

More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness. [1] Symptomatic nonpolio virus infections include the following:

  • Pleurodynia
  • Myopericarditis
  • Acute hemorrhagic conjunctivitis (AHC)
  • Nonspecific febrile illness
  • Aseptic meningitis
  • Herpangina
  • Hand-foot-and-mouth disease (HFMD) [2]
  • Encephalitis

Physical examination findings in enteroviral disease vary greatly depending on the type of illness and etiologic agent, as follows:

  • Nonspecific febrile illness – Physical findings are those of general viral illness; mild pharyngeal erythema or conjunctivitis may be present
  • Pleurodynia – Paroxysmal chest pain is characteristic, has no prodrome, and begins with an abrupt onset of spasmodic pain, typically over the lower part of the rib cage or the upper abdominal region; fever often occurs within 1 hour of the onset of pain and subsides as the pain recedes; during paroxysms, respirations are rapid and shallow; the pain is reproducible, and patients appear healthy between paroxysms of pain; auscultation may reveal a pleural friction rub
  • Myopericarditis – The most common symptoms are dyspnea, chest pain, fever, and malaise [3] ; precordial pain may be sharp or dull and is often exacerbated by recumbency; a pericardial friction rub, if present, is transient; signs of congestive heart failure are present in 20% of cases [4]
  • AHC – The hallmark physical findings include ocular erythema and subconjunctival hemorrhage, which seems to be more profuse in young patients [5] ; palpebral edema, chemosis, and ocular discharge may also be noted; preauricular lymphadenopathy is an associated finding
  • Aseptic meningitis – Meningeal signs (nuchal rigidity, bulging fontanelles in infants) may be present; rash may develop; approximately 5%-10% of infants experience complications such as febrile seizures, complex seizures, lethargy, coma, and movement disorders early in the course [6]
  • Encephalitis – Manifestations range from lethargy, drowsiness, and personality change to seizures, paresis, coma, motor seizures, hemichorea, and acute cerebellar ataxia [7]
  • Herpangina – Punctate macular lesions appear the on oral mucosa, most commonly the anterior tonsillar pillar and soft palate; the lesions evolve into vesicles and eventually ulcerate
  • HFMD – Vesicular lesions develop on the hands and feet and in the oral cavity; hands are involved more commonly than feet; the skin lesions consist of mixed papules; clear vesicles appear gray and are surrounded by erythematous rings; lesions are tender and resemble those of herpes simplex or varicella zoster infection; they resolve in approximately 1 week [2]

Nonparalytic polio

  • Signs of meningeal irritation are present
  • Kernig and Brudzinski signs may be present
  • In infants, the head drop sign can be elicited

Paralytic polio

  • In early-stage disease, reflexes are normally active; a change in the character of reflexes precedes paralysis by 12-24 hours
  • Superficial reflexes decrease first, followed in 8-24 hours by loss of deep tendon reflexes
  • Paralysis is flaccid and characteristically asymmetric in distribution, with proximal limb muscles involved more than distal muscles and the lower extremities affected more commonly than the upper extremities

See Clinical Presentation for more detail.

Diagnosis

Diagnosis of enterovirus infections is often clinical. Laboratory diagnosis can be achieved with the following:

  • Serological tests – Have multiple drawbacks; infrequently used
  • Viral isolation by cell culture – CSF, blood, or feces can be sampled, depending on the site affected; yield is increased if multiple sites are sampled
  • Polymerase chain reaction (PCR) – Provides rapid results; the best diagnostic test for use in CSF
  • In myopericarditis, chest radiography, echocardiography, and ECG can be used for diagnosis

See Workup for more detail.

Management

Treatment is as follows:

  • Management is supportive and addresses symptoms (eg, bed rest, analgesics)
  • No antiviral medications are currently approved for the treatment of enterovirus infections
  • Immunoglobulins have been used therapeutically and prophylactically for enteroviral CNS infections in neonates and immunocompromised hosts, with mixed results [8]
  • Abortive and nonparalytic polio can be managed at home, but patients with paralytic polio require hospitalization

See Treatment and Medication for more detail.

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Background

The human enteroviruses are ubiquitous viruses that are transmitted from person to person via direct contact with virus shed from the gastrointestinal or upper respiratory tract. The enteroviruses belong to the Picornaviridae family of viruses and are traditionally divided into 5 subgenera based on differences in host range and pathogenic potential. [9] Each subgenus contains a number of unique serotypes, which are distinguished based on neutralization by specific antisera. The subgenera include polioviruses, coxsackievirus (groups A and B), and echoviruses.

A total of 72 serotypes were originally identified by conventional methods; 64 serotypes remain after recognition of redundant serotypes. Three serotypes comprise the polioviruses, 23 serotypes comprise coxsackievirus group A, 6 serotypes comprise coxsackievirus group B, and 29 serotypes comprise the echoviruses. A new classification scheme has been adopted that divides all nonpolio enterovirus into 4 groups designated A through D based on the homology within RNA region coding for the VP1 capsid protein. [10] More recently, many new serotypes that are not included in the original classification have been characterized by molecular methods, bringing the number of known serotypes to more than 90. [11, 12]

Virology

The enteroviruses are icosahedral nonenveloped viruses that are approximately 30 nm in diameter.

They have a capsid composed of 60 subunits each formed from 4 proteins (VP1 to VP4).

They are stable at a pH from 3-10, distinguishing them from other picornaviruses (including rhinoviruses), which are unstable below pH 6.

A linear, single-strand RNA genome of about 7.5 kb is enclosed by the capsid; the translation product is a single polyprotein that is cleaved after translation by viral-coded proteases into the structural proteins (VP1 to VP4), RNA polymerase, proteases, and other nonstructural proteins. [13]

Enteroviruses resist lipid solvents, ether, chloroform, and alcohol. They are inactivated at temperatures above 50°C but remain infectious at refrigerator temperature.

Molar MgCl2 reduces thermolability at higher temperatures.

The viruses are inactivated by ionizing radiation, formaldehyde, and phenol.

Enteroviruses cause a wide range of infections. Poliovirus, the prototypical enterovirus, can cause a subclinical or mild illness, aseptic meningitis, or paralytic poliomyelitis, a disease that has been eradicated in the United States and other developed countries. The nonpolio viruses (group A and B coxsackieviruses, echoviruses, enteroviruses) continue to be responsible for a wide spectrum of diseases in persons of all ages, although infection and illness occur most commonly in infants.

Coxsackievirus infection is the most common cause of viral heart disease. Group A coxsackieviruses may cause flaccid paralysis, while group B coxsackieviruses cause spastic paralysis. Other diseases associated with group A coxsackievirus infections include hand-foot-and-mouth disease (HFMD) and hemorrhagic conjunctivitis, while group B coxsackievirus is associated with herpangina, pleurodynia, myocarditis, pericarditis, and meningoencephalitis. Aseptic meningitis and the common cold are associated with both groups.

Diseases caused by echoviral infections range from the common cold and fever to aseptic meningitis and acute hemorrhagic conjunctivitis (AHC).

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Pathophysiology

Enteroviruses are transmitted predominantly via the fecal-oral route. However, there are some exceptions, including coxsackievirus A21, which is spread mainly by respiratory secretions, [14] and enterovirus 70, which is shed in tears and spread via fingers and fomites. [15]

Upon entry into the oropharynx, the virus replicates in submucosal tissues of the distal pharynx and alimentary tract. [16] Viral particles are shed in the feces and in upper respiratory tract secretions for days prior to symptom onset. The average incubation period is 3-10 days, during which the virus migrates to regional lymphoid tissue and replicates. Minor viremia results, which is associated with the onset of symptoms and viral spread to the reticuloendothelial system (spleen, liver, bone marrow). [17]

Dissemination to target organs follows, and viral replication in target organs produces the major viremia with possible secondary seeding of the CNS. Potential target organs include the skin and CNS. Infectious virus is shed from the upper respiratory tract for 1-3 weeks and from the feces for 3-8 weeks. Enteroviruses undergoes a high rate of mutation during replication in the gastrointestinal tract, where single-site mutations can occur in the 5' noncoding region of the attenuated polioviruses; this can lead to prolonged excretion and neurovirulence. [18]

The neuropathy of paralytic diseases caused by enteroviruses is due to direct cellular destruction. Neuronal lesions occur mainly in anterior horn cells of the spinal cord. The 3 serotypes of poliovirus all bind to the cell surface receptor CD155.

Immunity and immune response

Immunity to enterovirus is serotype-specific. Intact humoral immunity is required for the control and eradication of enteroviral disease.

T lymphocytes do not contribute to viral clearance and, in coxsackievirus B3 myocarditis, may contribute to myocardial inflammation. [19]

Humoral immunity (antibody-mediated) mechanisms operate both in the alimentary tract (to prevent mucosal infection) and in the blood (to prevent dissemination to target organs).

Secretory immunoglobulin A (IgA) appears in nasal and alimentary secretions 2-4 weeks after the administration of live-attenuated oral poliovirus vaccine (OPV) and persists for at least 15 years. [20] Upon re-exposure to infectious virus, high titers of secretory IgA antibodies prevent or substantially reduce poliovirus shedding; higher secretory IgA titers lead to better immunity. [20]

Immunoglobulin M (IgM) antibodies appear as early as 1-3 days after enteroviral challenge and disappear after 2-3 months. [20]

Immunoglobulin G (IgG) antibody, which is generally detected 7-10 days after infection, is mostly of the IgG1 and IgG3 subtypes. Serum neutralizing IgG antibodies persist for life after natural enteroviral infections. [21]

Macrophage function is also a critical component of the immune response in enteroviral infections; ablation of macrophage function in experimental animals markedly enhances the severity of coxsackievirus B infections. [22]

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Frequency

United States

Nonpolio enteroviruses are responsible for 10-20 million symptomatic infections per year and are more prevalent among children of lower socioeconomic class, probably because of crowding, poor hygiene, and opportunities for fecal contamination.

AHC was first recognized in the United States in 1981 during an epidemic in Florida; few cases have been reported since. The prevalence is higher in southern areas than in northern areas.

Between 2002 and 2004, echoviruses 9 and 30 were the most commonly reported enterovirus serotypes in the United States. [23] In contrast, other enterovirus serotypes (eg, echovirus 1, coxsackievirus B6, and enteroviruses 68 and 69) are rarely reported and appear to have little epidemic potential. [24] However, difficulty in isolation of enterovirus 68 (EV68, EV-D68, EVD-68, HEV68) may bias the data, leading to an underestimation of its prevalence. [25]

A 2014 outbreak of enterovirus 68 (also called enterovirus D68) has been reported in at least six US states, including Colorado, Illinois, Iowa, Kansas, Kentucky, and Missouri, among others. In China, it had been noted since 2016. [26] From mid-August to September 11, 2014, 82 cases of enterovirus 68 infection had been confirmed by the CDC in the outbreak, although the total number of confirmed cases is higher since this figure does not include cases confirmed by individual state laboratories. This outbreak has been notable for its high number of hospitalizations involving infected children. [27] It is probable that there were different EV-D68 strains in China and America with mutations accounting for different prevalence. [26]  Foster et al have suggested that DV-68 infection may act as a trigger for childhood asthma. [28]

Coxsackievirus A is likely underrepresented because only some serotypes are readily isolated in cell culture. [29]

National or regional outbreaks of aseptic meningitis are occasionally reported, such as the echovirus 30 outbreaks in the United States between 1989 and 1992 and in 2003 and echovirus 13 and echovirus 18 outbreaks in 2001. Aseptic meningitis is no longer a nationally notifiable disease in the United States.

International

Enteroviruses are distributed worldwide and are influenced by season and climate. Infections occur in summer and early fall in temperate areas, while tropical and semitropical areas bear the brunt all year.

AHC occurs as epidemics in tropical countries during the hot and rainy season. It was first recognized in 1969 in Ghana (Apollo disease) and Indonesia. AHC is also epidemic in India and the Far East.

The worldwide prevalence of poliomyelitis has decreased significantly because of improved economic conditions and availability of vaccines. The last case of wild polio in the Americas occurred in Peru in 1991. In 1994, the World Health Organization declared polio eradicated from the Western Hemisphere. In 2000, 7 cases of poliomyelitis due to a mutated polio strain related to oral polio vaccine were reported from Haiti and the Dominican Republic. Polio remains a significant disease in the developing world, and, in 2003, 6 endemic countries were identified: Afghanistan, Egypt, India, Niger, Nigeria, and Pakistan.

In 2008, 1,652 confirmed cases of paralytic polio were reported worldwide. Polio is endemic in 4 countries: Afghanistan, India, Nigeria, and Pakistan. In addition, 14 other previously polio-free countries (Angola, Burkina Faso, Benin, Central Africa Republic, Chad, Côte d'Ivoire, The Democratic Republic of Congo, Ghana, Ethiopia, Nepal, Niger, Sudan, Tango) have reported cases in 2008-2009 (114 cases through August 2009) as a result of importations. [30, 31] As of September 2009, 969 cases of polio (including wild polio strains and oral vaccine–derived) had been reported in endemic and nonendemic countries. [32]

In a Korean study of children during an outbreak of aseptic meningitis, echovirus 6 or 30 infection was the most common manifestation. [33]

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Mortality/Morbidity

More than 90% of infections caused by the nonpolio enteroviruses are asymptomatic or result in only an undifferentiated febrile illness. [1]

Myopericarditis carries a mortality rate of 0%-4%. Myocarditis carries a higher mortality rate than pericarditis. Additionally, murine model studies have suggested that a deficiency of complement receptors 1 and 2 leads to increased morbidity in coxsackie B3 infections, including myocarditis, dilated cardiomyopathy, and fibrosis. [34]

Prior to the vaccine era, the mortality rate in polio epidemics was 5%-7%.

The overall risk of OPV-related disease is estimated to be 1 case per 2.6 million doses of OPV. The inactivated poliovirus vaccine (IPV) was incorporated into the routine polio vaccination in Europe and Canada in the 1980s. IPV has been used in the United States since 2000; OPV is no longer used in the United States.

Despite the risk of OPV-related paralysis, it is still the preferred vaccine for global polio eradication in developing nations (see Deterrence/Prevention).

Sex

The male-to-female ratio of myopericarditis is 2:1. The risk of cardiac involvement is higher during pregnancy and immediately postpartum.

The prevalence of polio infection is equal in boys and girls, although paralysis is more common in boys. Among adults, women are at increased risk of infection and the postpolio syndrome.

Aseptic meningitis is approximately twice as common in males as in females.

Age

Enteroviral infections are most common in young children. Herpangina primarily affects children aged 3 months to 16 years. Poliomyelitis is observed in children younger than 15 years. Aseptic meningitis due to enteroviral infection is more common in infants than in adults. Most cases of pleurodynia occur in children and adults younger than 30 years.

Myopericarditis is most prevalent in young adults, especially those who are physically active. AHC is most prevalent in adults aged 20-50 years.

Neonates are at high risk for severe sepsis due to enterovirus infections.

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