Enteroviruses 

Updated: Mar 01, 2018
Author: Robert A Schwartz, MD, MPH; Chief Editor: Michael Stuart Bronze, MD 

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.

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).

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]

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]

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.

 

Presentation

History

Polio

Disease due to wild-type poliovirus infection no longer occurs in the Western Hemisphere, and a World Health Organization (WHO) international eradication program is making significant progress in the rest of the world.[32]

Patients with abortive polio present with symptoms similar to those of other viral infections, including fever, headache, sore throat, loss of appetite, vomiting, and abdominal pain. Neurologic symptoms are typically not reported.

The symptoms of nonparalytic polio are similar to those of abortive polio but are more intense. Patients report stiffness of the posterior muscles of the neck, trunk, and limbs.

Paralytic polio

Paralytic polio presents similarly to nonparalytic polio. It 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. Exercise increases the severity of paralytic polio, especially during the first 3 days of the major illness. Intramuscular injections or skeletal muscle injury predisposes to localization of polio to that extremity (termed provocation poliomyelitis).

Spinal: Patients have a prolonged prodrome, with features of aseptic meningitis followed in 1-2 days by weakness and, eventually, paralysis.

Bulbar: Cranial nerves are involved, most commonly IX, X, and XII. Tonsillectomy increases the risk of bulbar polio. Patients are unable to swallow smoothly. They accumulate pharyngeal secretions, have a nasal twang to the voice, and develop paralysis of vocal cords, causing hoarseness, aphonia, and, eventually, asphyxia.

Polioencephalitis: This form is principally reported in children. Unlike in other forms of polio, seizures are common and paralysis may be spastic.

Nonpolio viruses

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

Pleurodynia

Group B coxsackieviruses, particularly B3 and B5, are the most important causes of epidemic pleurodynia. Multiple family members may be affected.[35, 36]

Pleurodynia manifestations include a sudden onset of fever accompanied by muscular pain in the chest and abdomen.[37] The pain is spasmodic in nature, with spasms lasting 15-30 minutes and worsening during inspiration or coughing. This paroxysmal pain is characteristically associated with fever, peaking within 1 hour after onset of each paroxysm and subsiding with the subsequent paroxysm. Headache, nausea, and vomiting are also frequently reported.

Myopericarditis

Enteroviruses appear to be the most common viral cause of myopericarditis and account for at least half of all cases of acute myopericarditis.

Neonatal infections typically develop within the first week of life, and involvement is predominantly myocardial. In contrast, older children and adults usually present with symptoms of pericarditis.

The typical presentation in adolescents and adults is shortness of breath, chest pain, and fever 1-2 weeks following an upper respiratory tract infection. Chest pain may be dull or sharp; it is worsened by inspiration and may improve with sitting and leaning forward. It can be differentiated from angina by lack of response to nitroglycerin.

Enteroviral myocarditis can present as acute myocardial infarction associated with arrhythmias and heart failure. Some patients with myocardial infarction who have normal findings on coronary angiographic studies have been shown to have myocarditis by radiolabeled antimyosin antibody cardiac scanning.[38]

Acute hemorrhagic conjunctivitis

This highly contagious ocular infection can cause large-scale epidemics. AHC was first described in 1969. Enterovirus 70 is the most common etiology in epidemics. Coxsackievirus A24 causes a similar disease. AHC was initially recognized in Ghana and Indonesia and is now epidemic in India and the Far East.[39]

The first reported outbreak of AHC in United States was Key West, Florida, in 1981; subsequently, 2,500 cases were reported in Miami. Since then, with the exception of few imported cases, AHC activity has not been reported in the United States.[40]

The mode of transmission is from finger or fomite to eye. AHC is highly contagious, and crowding and unsanitary conditions favor spread. Reuse of water for bathing and sharing of towels have been implicated as factors contributing to the spread of infection.[41, 15]

Onset is abrupt, and the most common symptoms include ocular pain and burning, swelling of the eyelids, and the sensation of a foreign body in the eye. Patients may also experience photophobia and watery discharge. The other eye becomes involved within hours of the first eye.

Nonspecific symptoms such as fever, malaise, and headache may be present. The symptoms typically improve by the second or third day of infection, and recovery is complete within 7-10 days.

Nonspecific febrile illness

This is the most common presentation of enterovirus infection.

More than 90% present with a nonspecific febrile illness that manifests as sudden fever (temperature, 101-104°F). The fever may last for as long as a week and may show a biphasic pattern.[1]

Patients may also report myalgia, headache, sore throat, nausea, vomiting, mild abdominal discomfort, and diarrhea.

Human enterovirus 68 infection in children may produce a respiratory outbreak characterized by pneumonia and wheezing.[42]

Aseptic meningitis

Enteroviral infections (group B coxsackievirus and echovirus) account for 90% of cases of aseptic meningitis in patients younger than one year and 50% of cases in older children and adults.[43, 44]

The clinical presentations of aseptic meningitis vary greatly. Prodromal symptoms include fever, chills, headache, photophobia, and nuchal rigidity. Rash and upper respiratory tract symptoms may also occur. In infants, fever and irritability are the most common symptoms.[6]

Fever and meningeal signs subside within 2-7 days.

Enterovirus 71, which causes HFMD, has also been associated with a particularly more aggressive and, in some instances, fatal CNS infection in children. It manifests as flaccid motor paralysis and brain stem encephalitis. Large outbreaks were reported in the late 1990s in Eastern Europe, Russia, Thailand, and Taiwan.[45]

Most of the enterovirus-positive 758 children in a Korean outbreak experienced fever, headache, vomiting, and neck stiffness, although some also showed cold symptoms, sore throat, altered mental status, and seizures.[33] More than 80% of these had either echovirus types 6 or 30. The majority recovered uneventfully.

Herpangina

Coxsackie A virus is the main etiologic agent of herpangina, described as a vesicular enanthem of the tonsillar fauces and soft palate that principally affects children aged 3-10 years.[46] Other serotypes have been isolated including enterovirus 71 (EV71), which has cause recent outbreaks and epidemics in South-East Asia[47]

Symptoms include sudden onset of fever, sore throat, and difficulty swallowing, followed a day later by a painful vesicular eruption of the oral mucosa. The posterior pharynx and tonsils may also be involved. Most disease occurs in the summer.

Patients may report anorexia, malaise, irritability, headache, backache, and diarrhea. Symptoms resolve in 3-4 days.

Hand-foot-and-mouth disease

This is mainly a disease of children; most patients are younger than 10 years. Epidemics of HFMD occur approximately every 3 years.

Coxsackievirus A16 is the most common etiologic agent, although enterovirus 71 and numerous other coxsackievirus serotypes may also cause the disease.[2]

Following an incubation period of 3-6 days, patients experience prodromal symptoms such as fever, cough, sore throat, malaise, and anorexia. The prodrome lasts from 12-36 hours; afterward, vesicular eruptions of the hands, feet, and oral cavity develop. This may cause decreased oral intake in young children. The lesions self-resolve within 5-7 days.

Infection with enterovirus 71 may be accompanied by severe neurologic disease including encephalitis, meningitis, and poliolike paralysis.[47]

Encephalitis

Frank encephalitis is an unusual manifestation of enterovirus infection.[48]

Echovirus 9 is the most common etiologic agent.

Clinical manifestations have ranged from lethargy, drowsiness, and personality change to seizures, paresis, and coma. Children with focal encephalitis present with partial motor seizures, hemichorea, and acute cerebellar ataxia; this may mimic herpes simplex encephalitis.[49, 50]

Nonpoliovirus paralytic disease

Enterovirus 71 and coxsackievirus A7 have been associated with large outbreaks of poliomyelitislike disease in Russia, Eastern Europe, Thailand, and Taiwan.[45] Some cases have manifested as brainstem encephalitis or noncardiogenic pulmonary edema, with some having a fatal course.

Paralytic disease caused by nonpolioviruses other than enterovirus 71 is usually less severe and is associated with paralysis. It manifests as muscle weakness and complete unilateral oculomotor palsy.

Guillain-Barré syndrome and transverse myelitis has been reported in a small number of patients infected with coxsackievirus serotypes A2, A5, A9, and B4 and with echovirus serotypes 5, 6, and 22.[51]

Neonatal infections

Refer to Medscape Reference article Pediatric Enteroviral Infections.

Physical

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 one 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] Pain in the precordial area maybe sharp or dull and is often exacerbated by the recumbency position. A pericardial friction rub is transient, if present. 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 in AHC.

  • Aseptic meningitis: Meningeal signs (nuchal rigidity, bulging fontanelles in infants) may be present, along with a positive Kernig and/or Brudzinski sign. Some patients develop a rash. Adults may experience a more prolonged period of headache and fever than children.[52] Approximately 5%-10% of infants with aseptic meningitis 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: Examination of the oral mucosa reveals punctate macular lesions that evolve into vesicles and eventually ulcerate. The most common site of involvement is the anterior tonsillar pillar and soft palate (mimics pharyngitis or tonsillitis). The lesions are tender and subside within one week.

  • 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 one week.

  • The coxsackievirus A6 (CVA6)–associated North American enterovirus outbreak of 2011-2012 was evaluated.[53] Atypical HFMD was noted as a vesiculobullous and erosive eruption, with 61% of patients having the rash involving more than 10% body surface area in a perioral, extremity, and truncal distribution in addition to palms, soles, and buttocks. In half the patients, there was an accentuation in areas of eczematous dermatitis. Other morphologic patterns included those of Gianotti-Crosti disease in 37% and petechial/purpuric eruptions in 17%.

  • Poliomyelitis

    • Nonparalytic polio: Signs of meningeal irritation are present, and patients may have positive Kernig and Brudzinski signs. 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 are the first to decrease, followed in 8-24 hours by loss of deep tendon reflexes. The resultant paralysis is flaccid and characteristically asymmetric in distribution. Proximal limb muscles are involved more than distal muscles. The lower extremities are affected more commonly than the upper extremities.

  • Orchitis: In some remote cases, the presentation of coxsackievirus B infection clinically resembles mumps orchitis.

Causes

The most common mode of transmission of enteroviruses is via the fecal-oral route. Poor sanitation, low socioeconomic status, and crowded living conditions all facilitate the spread of infection. Direct contact with feces occurs with activities such as diaper changing. Indirect transmission due to poor sanitary conditions may occur via numerous routes, including via contaminated water, food, fingers, fomites, or contaminated ophthalmological instruments (eg, AHC).

Respiratory-oral spread may also be the mode of transmission for coxsackievirus A21 and other coxsackievirus serotypes.

Transmission of enteroviruses has been described among travelers swimming in sewage-contaminated seawater.[54]

 

DDx

Diagnostic Considerations

Acute hemorrhagic conjunctivitis

Adenovirus keratoconjunctivitis

Gonococcal conjunctivitis

Myopericarditis

Acute myocardial infarction

Angina

Ischemic and nonischemic cardiomyopathy

Other viral pericarditis

Aseptic meningitis

Arbovirus infection

Lyme disease

Rocky Mountain spotted fever

Ehrlichiosis

Incompletely treated bacterial meningitis

Syphilis

Tuberculosis meningitis

Sarcoidosis

Hand-foot-and-mouth disease

Herpes simplex

Aphthous stomatitis

Erythema multiforme

Atypical varicella

Abortive polio

Aseptic meningitis

Paralytic polio

Guillain-Barré syndrome

Botulism

Arthropod-borne viral encephalitis

Herpangina

Bacterial tonsillitis

Aphthous stomatitis

Other viral tonsillitis

Oral herpes simplex infections

Pleurodynia

Pneumonia

Pulmonary infarction

Rib fracture

Costochondritis

Herniated intervertebral disc

Renal colic

Myocardial infarction

Prodromal phase of zoster

Acute abdomen

Empyema

Guillain-Barré syndrome is an acute demyelinating polyneuropathy and, in the postpolio era, is the most common cause of generalized paralysis. The major symptom is rapidly progressive paralysis, which, unlike in polio, is symmetrical. Paralysis of the lower extremities is followed by paralysis of the upper extremities, and both proximal and distal muscle groups are involved. Deep tendon reflexes are initially reduced and are later absent. A mild sensory disturbance or paresthesia occurs. The cerebrospinal fluid (CSF) typically has an elevated protein level and a normal cell count (albuminocytologic dissociation).

The cutaneous manifestations of human enterovirus infections include widespread blistering mucocutaneous reactions without any suspected drug causality.[55] A new variant of coxsackievirus A6 has been identified in the Republic of China as the causative agent for severe mucocutaneous blistering reactions similar to what one may see with severe cutaneous adverse reactions, characterized as resembling the Stevens-Johnson syndrome complete with erythema multiform–like plaques. In addition, the histologic patterns was that of erythema multiforme major/Stevens-Johnson syndrome.

Differential Diagnoses

 

Workup

Laboratory Studies

Diagnosis of enterovirus infections is often clinical. Laboratory diagnosis can be achieved with serological tests, viral isolation by cell culture, and polymerase chain reaction (PCR).

Serology

The microneutralization test is the most widely used method for detecting antibodies to enteroviruses. Serological examination reveals a 4-fold increase in antibodies to enteroviruses between the acute and convalescent phases of illness.[56] This diagnostic modality is infrequently used since it is serotype-specific, relatively insensitive, poorly standardized, labor intensive, and too slow for clinical purposes.

Viral isolation

The virus can be isolated from CSF, blood, or feces, depending on the site affected, and the yield is increased if multiple sites are sampled. Enterovirus produces a characteristic cytopathic effect in cultured cells. Poliovirus is easily cultured from stool and nasopharyngeal secretions, but isolation from the CSF is more difficult. The cytopathic effect is confirmed by indirect immunofluorescence using a broadly specific monoclonal antibody. The sensitivity of viral culture ranges from 60%-75%.[57]

Polymerase chain reaction

This rapid test is highly sensitive and specific for detecting enteroviral RNA in CSF specimens, with a sensitivity of 100% and specificity of 97%.[58, 59] PCR provides rapid results and is the best diagnostic test for use in CSF but is limited by availability in some areas and cost in underdeveloped regions.[60]

In 2008, a multiplex real-time PCR (RT-PCR) assay was developed for simultaneous detection, identification, and quantification of enterovirus 70 and a coxsackievirus A24 variant. The novel technique is used as a rapid diagnostic method to evaluate for enterovirus-related AHC.[61]

Cardiac enzyme levels

Cardiac enzyme levels may be elevated in persons with myopericarditis, indicating myocardial damage.

CSF analysis

The CSF profile in patients with aseptic meningitis usually reveals a mildly elevated white blood cell count, and the differential invariably shifts to a predominance of lymphocytes during the initial 1-2 days of illness. Glucose levels are normal or mildly decreased,[62] while the protein level is normal or slightly increased.

Imaging Studies

Chest radiography: In patients with myopericarditis, chest radiography may reveal cardiomegaly secondary to pericardial effusion or cardiac dilation. In pleurodynia, chest radiographic findings are normal.

Echocardiography: Transient wall motion abnormalities may be detectable in mild cases. Severe cases may demonstrate acute ventricular dilation and reduced ejection fraction.

Other Tests

ECG: Nonspecific ST-T changes may be observed in persons with myopericarditis. Severe disease may cause Q waves, ventricular tachyarrhythmias, and heart block. ECG findings may demonstrate evolution through several stages of myopericarditis, as follows:

  • Stage I - Diffuse ST elevation with PR depression

  • Stage II - Normalization of ST and PR segments

  • Stage III - Deep symmetric inversion of T waves

  • Stage IV - May revert to normal or permanent T-wave inversions

Electroencephalography: This test may be useful for evaluating the extent and severity of illness in patients with encephalitis.

Ophthalmic slit-lamp examination: In persons with AHC, corneal erosions may be visualized using a fluorescein stain. Enterovirus 70 and coxsackievirus A24 can often be recovered from conjunctival swabs during the first 3 days of infection.

Histologic Findings

Histopathologic findings in most enterovirus infections are usually nonspecific, consisting primarily of lymphocytic infiltrates and cellular destruction.

Histologic findings in patients with polio have been well studied. Evidence of infection is pronounced in the spinal cord, medulla, pons, and mid brain. Neuronal destruction is observed, along with an inflammatory infiltrate composed of lymphocytes, macrophages, and polymorphonuclear leukocytes.

 

Treatment

Medical Care

Polio management is supportive in nature, as follows:

  • Abortive polio: Treatment with bed rest and minimal exertion may be done at home. Supportive treatment with analgesics and sedatives may be used.

  • Nonparalytic polio: Management is similar to that of abortive polio. Combine analgesic therapy with hot packs for pain relief.

  • Paralytic polio: In contrast to abortive and nonparalytic polio, which can be managed at home, patients with paralytic polio require hospitalization.

  • Bed rest is required during the early stages of the disease because exertion may worsen the paralysis.

  • Applying hot packs to affected muscles may alleviate pain.

  • Align the body in a neutral position to minimize deformity. Patients should start physical therapy soon after the resolution of pain. Physical therapy should include both active and passive exercises.

  • Mechanical ventilation may be required if respiratory muscles are affected.

  • Postural drainage and suction should be implemented in mild bulbar polio.

  • Patients with weakness or paralysis of the bladder may be treated with cholinergic agents, the sound of running water, or catheterization.

Pleurodynia

Treatment is symptomatic, using analgesics and heat application for pain relief. Severe pain may require opiate analgesics.

Aseptic meningitis

Treatment is symptomatic, with analgesics for headache relief. Headache is often severe and prolonged in adults; potent analgesics should be administered, when necessary.

Myopericarditis

Treatment is mainly supportive in nature and involves management of pericardial pain, pericardial effusion, arrhythmias, and heart failure.

Bed rest is important since exercise can increase the degree of myocardial necrosis.

Intravenous immunoglobulin (IVIG) therapy has shown some benefit in small case-control studies. Nevertheless, most reports lack statistical significance, and randomized trials are needed.[63, 64]

Capsid-binding inhibitors belong to a class of drugs that have shown benefit in some immunosuppressed patients with myocarditis. However, these drugs are not available for use in the United States.[65]

Corticosteroids yield little or no benefit, and immunosuppressive therapy is contraindicated during the acute phase of viral myocarditis because they have been shown to cause clinical deterioration.[66]

Acute hemorrhagic conjunctivitis

Treatment is primarily symptomatic in nature.

Antimicrobial agents are not indicated unless bacterial superinfection occurs. Corticosteroids are contraindicated.

Cold compresses may be used, along with antihistamine/decongestant eye drops.

Herpangina and hand-foot-and-mouth disease

Symptomatic treatment for sore throat is the mainstay of treatment, including analgesics, topical anesthetics, mouth wash, and saline rinses.

Viscous lidocaine (2% solution) may be helpful.

Surgical Care

Cardiac transplantation may be required in severe cases of dilated cardiomyopathy due to enteroviral infection.

Consultations

Consultation with a physiatrist is helpful to plan specific exercise programs, to direct physical therapy, and to provide adaptive equipment for patients with paralytic polio.

Consultation with a cardiologist may be requested in myopericarditis for management of arrhythmias.

Consultation with a cardiovascular surgeon may be required for the management of complicated pericardial effusions and in some cases for cardiac transplantation.

Consultation with an ophthalmologist is appropriate for AHC.

Consultation with a neurologist is recommended in cases of paralytic polio.

Physical and occupational therapists help patients with polio to establish a safe exercise program, to adapt the home environment, and to use mechanical aids (eg, grab bars).

Consultation with an infectious disease specialist may be useful in cases of unexplained aseptic meningitis or myopericarditis.

Diet

Patients with paralytic polio should be encouraged to maintain a high fluid intake.

The application of hot packs leads to sweating, meaning that fluids need to be replenished.

High fluid intake protects against nephrocalcinosis and urinary tract infections due to prolonged immobilization.

A diet rich in L-carnitine is under research as a treatment for postpolio syndrome.

Patients with herpangina should consume soft bland foods and fluids and avoid pain-inducing salty foods and citrus fruits.

Activity

Bed rest is required for patients in the early stages of paralytic polio. Physical therapy should begin as soon as possible after the resolution of pain. Isometric exercises for select muscle groups can help increase muscle strength. Muscle capacity can also be increased with bracing and orthotics.

 

Medication

Medication Summary

Management is supportive and addresses symptoms. No antiviral medications are currently approved for the treatment of enterovirus infections.

 

Follow-up

Inpatient & Outpatient Medications

Pleconaril interferes with enterovirus attachment and uncoating by binding to the virus protein capsid. It was once the most promising candidate for the treatment of enterovirus infections because of its oral bioavailability, penetration into the CNS, and efficacy in reducing the duration of symptoms and morbidity in neonatal sepsis, adult meningitis, and perimyocarditis; however, efficacy has not been definitively established.[67, 65] Until 2003, when the US Food and Drug Administration (FDA) declined its approval, pleconaril had been used on a compassionate basis for treatment of myocarditis and aseptic meningitis in infants. Pleconaril in an intranasal form is currently awaiting FDA approval for the treatment of rhinoviral infections, which although usually self-limited, may persist untreated, particularly in immunosuppressed individuals.[68]

Immunoglobulins have been used therapeutically and prophylactically for enteroviral CNS infections in neonates and immunocompromised hosts, with mixed results.[8] Pre-exposure prophylaxis with immunoglobulins is known to reduce the risk of paralysis in patients with poliovirus infections.

Deterrence/Prevention

Hygienic measures such as hand washing and adequate disposal of infected secretions help prevent the spread of enteroviral infections.

Poliovirus vaccines have been instrumental in the effort to eradicate polio; the vaccine is available in 2 forms. Considerations are as follows:

  • The OPV is a live attenuated vaccine that contains all 3 serotypes. It was developed by Sabin. OPV administration decreases replication of the virus in the small intestine and increases production of high titers of IgA in the mucosa. The advantages of OPV include easy administration, stimulation of local and generalized immunity, and herd immunity. Adverse effects include vaccine-associated paralytic poliomyelitis[69] and seroconversion rates lower than those achieved with IPV. OPV should not be administered to immunocompromised patients or to household contacts of these patients.

  • OPV is used in developing nations because of it lower cost, ease of administration, and superior secretory immunity in the GI tract in comparison to IPV.

  • IPV was originally developed by Salk in 1955. Current formulations of IPV are more immunogenic than those available before 1987. This vaccine elicits higher IgG antibody titers and has few adverse effects but is inferior to OPV in providing secretory immunity in the GI tract. It is the recommended polio vaccine in United States when the risk of vaccine-associated paralytic polio disease due to OPV exceeds that of wild-type polio disease. Higher costs for production and supply and the delivery route, along with the lack of herd immunity, makes its use less desirable in developing countries.

  • Combined immunization with OPV and IPV provides the highest serum level of antibody response, with equivalent mucosal immunity to that produced by OPV alone.[70]

The spread of AHC is prevented by hand washing and using separate towels.

Intensified efforts to eradicate polio have led to the introduction of new monovalent OPV type 1 (mOPV1) and type 3 (mOPV3) vaccines to more rapidly eliminate the final strains of poliovirus in circulation.

Further efforts to simplify administration of the two monovalent vaccines have resulted in the development of a bivalent oral polio vaccine (bOPV). This vaccine consists of live-attenuated (weakened) poliovirus strains of type 1 and type 3, which simultaneously target the two remaining types of wild poliovirus (type 1 and type 3).

Recent trials demonstrated the superiority of bOPV over tOPV and noninferiority to the respective mOPVs in achieving seroconversion.[71]

As of 2009, the use of bOPV or mOPVs as supplementary immunization activity to complement tOPV is recommended.[30]

Complications

Polio

Respiratory failure secondary to paralysis of respiratory muscles or to lesions of the respiratory center is a life-threatening complication of paralytic polio.

Pharyngeal paralysis may occur.

Myocarditis is rarely diagnosed clinically.

Gastrointestinal hemorrhage results from intestinal erosions and may require transfusion. Gastric dilation is abrupt in onset, and immediate gastric aspiration should be performed.

Hypertension is a common complication and may progress to hypertensive encephalopathy.

Postpolio syndrome occurs 3-4 decades after acute paralytic polio. It is characterized by muscle pain, worsening of prior weakness, or new paralysis. This is more common in women than in men.

Vaccine-associated poliomyelitis occurs in approximately 1 per 2.6 million people overall and in 1 per 750,000 people who receive the OPV.

Aseptic meningitis

Complications include lethargy, febrile seizures, and coma.

Nonpoliovirus paralytic disease

This is usually less severe than polio-associated paralysis.

Myopericarditis

Chronic dilated cardiomyopathy may result from past enteroviral infections, and cardiac transplantation may be required in severe cases.

In rare cases, chronic constrictive pericarditis develops 5 weeks to 1 year after resolution.

Acute hemorrhagic conjunctivitis

Secondary bacterial conjunctivitis may occur.

In severe cases, keratitis may occur and may last several weeks but is rarely permanent.

Paralysis (motor and/or sensory) may follow AHC by 2-5 weeks. It is clinically indistinguishable from polio, although it occurs exclusively in patients older than 20 years. Males are affected more frequently than females.[72]

Neurological complications of AHC occur in epidemics caused by enterovirus 70 but not by coxsackievirus A24.

Prognosis

Polio: Paralytic polio leads to permanent weakness in the affected limb. Permanent weakness occurs in approximately two thirds of patients. Postpolio syndrome is slowly progressive. In the epidemic era, poliomyelitis carried an overall mortality rate of 5%-10%.

Aseptic meningitis: Fever and signs of meningeal irritation usually resolve within 1-2 weeks in infants; some adults are ill for 2-3 weeks. Long-term prognosis is excellent.

Pleurodynia: Patients with epidemic pleurodynia completely recover.

Myopericarditis: The prognosis is good, and mortality rates in acute infection are low. Severe cases can result in dilated or restrictive cardiomyopathy, persistent electrocardiographic abnormalities, or congestive heart failure. Twenty percent of patients may have recurrent myopericarditis and develop chronic dilated cardiomyopathy. Infants are at a higher risk of developing long-term sequelae.

Patient Education

HFMD is very contagious, especially during the first week of the illness. The virus can still be spread weeks after symptoms have resolved. As a preventive measure, close contact with affected individuals should be avoided.

 

Questions & Answers

Overview

Which lab tests are performed in the diagnosis of enteroviruses?

What are enteroviruses?

What are the signs and symptoms of polio enteroviral infection?

What are the symptomatic nonpolio enteroviral infections?

Which physical findings are characteristic of enteroviral disease?

Which physical findings are characteristic of nonparalytic polio caused by enteroviruses?

Which physical findings are characteristic of paralytic polio caused by enteroviruses?

How are enteroviral diseases treated?

What are enteroviruses?

What is the virology of enteroviruses?

Which infectious diseases and conditions are caused by enteroviruses?

What is the pathophysiology of enteroviruses?

What is the immune response to enteroviral infections?

What is the prevalence of enteroviruses in the US?

What is the global prevalence of enteroviruses?

What is the mortality and morbidity associated with enteroviruses?

What is the sexual predilection of enteroviruses?

Which age groups have the highest prevalence of enteroviral diseases?

Presentation

Which clinical history findings are characteristic of nonparalytic polio caused by enteroviruses?

Which clinical history findings are characteristic of paralytic polio caused by enteroviruses?

What are the signs and symptoms of nonpolio enteroviral diseases?

Which clinical history findings are characteristic of enteroviral pleurodynia?

Which clinical history findings are characteristic of enteroviral myopericarditis?

Which clinical history findings are characteristic of acute enteroviral hemorrhagic conjunctivitis?

What is the most common clinical presentation of enterovirus infection?

Which clinical history findings are characteristic of enteroviral aseptic meningitis?

Which clinical history findings are characteristic of enteroviral herpangina?

Which clinical history findings are characteristic of enteroviral hand-foot-and-mouth disease?

Which clinical history findings are characteristic of enteroviral encephalitis?

Which clinical history findings are characteristic of nonpoliovirus paralytic disease?

Which physical findings are characteristic of enterovirus infection?

How are enteroviral infections transmitted?

DDX

How is Guillain-Barré syndrome differentiated from enteroviral disease?

Which conditions should be included in the differential diagnoses for enteroviruses?

How is Stevens-Johnson syndrome differentiated from enteroviral disease?

What are the differential diagnoses for Enteroviruses?

Workup

What is the role of cardiac enzyme measurement in the workup of enteroviral disease?

How is enterovirus infection diagnosed?

What is the role of serology in the workup of enteroviral diseases?

How are enteroviruses isolated in the workup of enteroviral disease?

What is the role of PCR in the workup of enteroviral disease?

What is the role of cerebrospinal fluid (CSF) analysis in the workup of enteroviral disease?

What is the role of imaging studies in the workup of enteroviral disease?

What is the role of ECG findings in the workup of enteroviral disease?

What is the role of electroencephalography in the workup of enteroviral disease?

What is the role of slit-lamp exam in the workup of enteroviral disease?

Which histologic findings are characteristic of enterovirus infection?

Treatment

How is enteroviral polio treated?

How is enteroviral pleurodynia treated?

How is enteroviral aseptic meningitis treated?

How is enteroviral myopericarditis treated?

How is acute enteroviral hemorrhagic conjunctivitis treated?

How are enteroviral herpangina and hand-foot-and-mouth disease treated?

What is the role of surgery in the treatment of enteroviral infections?

Which specialist consultations may be helpful in patients with enterovirus infections?

Which dietary modifications are used in the treatment of enteroviral diseases?

Which activity modifications are used in the treatment of enteroviral infections?

Medications

What is the role of medications in the treatment of enteroviral diseases?

Follow-up

Which medications are used in the treatment of enteroviral diseases?

How are enteroviral infections prevented?

What are the possible complications of polio?

What are the possible complications of enteroviral aseptic meningitis?

What are the possible complications of nonpoliovirus paralytic disease?

What are the possible complications of enteroviral myopericarditis?

What are the possible complications of acute enteroviral hemorrhagic conjunctivitis?

What is the prognosis of enteroviral diseases?

What is included in patient education about enteroviruses?