AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

The enterovirus (EV) genus is a member of the Picornaviridae family of small, icosahedral, single-stranded, positive-sense RNA viruses. The original classification of these viruses included polioviruses (PVs), coxsackie A and B viruses (CVA and CVB, respectively), echoviruses (Es), and EVs. These viruses have been reclassified, based largely on molecular properties, into 5 species, as follows:

• Poliovirus - PV1-PV3
• Human EV A (HEV-A) - CVA2-CVA9, CVA10, CVA12, CVA14, CVA16, and EV71
• Human EV B (HEV-B) - CVA9, CVB1-CVB6, E1-E7, E9, E11-E21, E24-E27, E29-E33, and EV69
• Human EV C (HEV-C) - CVA1, CVA11, CVA13, CVA15, CVA17-CVA22, and CVA24
• Human EV D (HEV-D) - EV68 and EV70, including several newly identified serotypes EV73-EV75^{1, 2} and EV77-EV78³

EVs usually cause transient, often subclinical, infections. They are also responsible for a wide variety of syndromes, including exanthematic fever, enteritis, encephalitis, aseptic meningitis, myocarditis, and respiratory tract infections. Coxsackieviruses, Es, and EV71 are also significant causes of cutaneous disease. A relationship between EV RNA and chronic fatigue syndrome has been described,⁴ and these viruses could initiate and perpetuate the immunological response seen in this entity.

Coxsackieviruses are separated into 2 groups: CVAs (24 serotypes) and CVBs (6 serotypes). CVAs are the primary etiologic agents of herpangina and hand-foot-and-mouth disease (HFMD). CVBs are associated with epidemic pleurodynia (ie, Bornholm disease), epidemic myalgia, myocarditis, and pericarditis. Bowles et al⁵ suggest that CVB may be an etiologic agent of juvenile dermatomyositis.

Zahorsky first described the clinical spectrum of herpangina in 1920. Later, CVA was isolated from pharyngeal washings and stool samples of patients with herpangina. Subsequently, many reports have confirmed this association. Robinson et al⁶ first isolated the CVA16 serotype in 1957 during a Canadian epidemic of exanthema and stomatitis. Two years later, Alsop et al⁷ used the term hand-foot-and-mouth disease to describe a similar eruption in England.

Es include 34 distinct serotypes, and at least half can cause a rash. Two specific skin diseases are associated with Es: Boston exanthem disease (BED) caused by E16 and eruptive pseudoangiomatosis (EP) caused by E25 and E32.

The following eMedicine and Medscape resources may be helpful:

• Enteroviral Infections (Pediatrics)
• Hand-Foot-and-Mouth Disease (Dermatology)
• Hand-Foot-and-Mouth Disease (Infectious Diseases)
• Pediatric Dermatology Resource Center

Pathophysiology

EVs are spread from person to person by oral-oral and fecal-oral routes and, presumably, may also be transmitted through direct contact with fluid from cutaneous and ocular lesions, because the virus can be isolated from these locations. Another source of infection could be swimming pools because EVs are easily detectable in natural and treated water sources. Their incubation period is usually 2-5 days. The viruses are highly contagious, and they are a common cause of widespread outbreaks. After the ingestion of infectious material, EVs are implanted and replicated in the alimentary tract (nasopharynx and ileum). If local replication is limited, the disease remains asymptomatic. If the virus passes into the regional lymphatic nodes and the reticuloendothelial system organs, minor or nonspecific disease may develop. Virus may also spread by the hematologic route, which results in a more severe and characteristically systemic illness.

Immune activation by the EV leads to the production of immunoglobulin M (IgM) type-specific antibodies, which may be detected in the serum 1 week after infection. They are responsible for neutralization and rapid elimination of the virus from the blood and other sites of implantation. Serum IgM antibodies can be detected for 6 months after the patient's recovery, and convalescent immunoglobulin G can be detected for 1-2 years. Most enteroviral infections confer lifelong immunity to the serotype-specific agent. In addition, antibodies to these related viruses are known to cross-react, and do so in different patterns, based on the country, serotype, and specific population, making comparisons of disease-based studies amongst these groups difficult.

Frequency

United States

Although EVs are responsible for an estimated 50 million infections and 30,000-50,000 hospitalizations each year, note that less than 1% of infections result in significant symptomatic illness and the vast majority of hospitalizations are for aseptic meningitis.

International

The frequency is not known, but some estimates put the number at 1 billion or more annually worldwide. Persons in lower socioeconomic groups are more frequently affected than other groups.

Mortality/Morbidity

Occasionally, cardiac and neurological complications occur. Deaths in neonates infected with EVs have been reported. They are usually the result of fulminant myocarditis.

Sex

Some authors suggest a slight male predominance, but this has not been confirmed.

Age

Enteroviral infections mainly affect children younger than 10 years, probably because they lack cross-reacting immunity resulting from repeated exposures, but they are not uncommon in adults.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Coxsackieviruses and Es cause many nonspecific exanthems and enanthems. An exanthem (ie, nonspecific morbilliform eruption) normally occurs 3-4 days before the characteristic enanthem (ie, oral vesicles) appears.

Seasonal distribution is a characteristic feature. In temperate climates, enteroviral infections are most common in the summer and autumn, whereas in tropical areas, they tend to occur year round. Some of the more specific clinical syndromes are described below.

• Herpangina  
• • The principle cause is CVAs (serotypes 2-6, 8, and 10). Other viral etiologies include CVBs (serotypes 1-4), Es, adenoviruses, and other EVs.
  • After an incubation period of approximately 4 days, the disease begins with acute onset of fever (temperature range, 38.5-40°C) accompanied by headache, sore throat, dysphagia, anorexia, and, occasionally, vomiting and abdominal pain.
• Hand-foot-and-mouth disease  
• • HFMD is most commonly associated with CVA16. HFMD is also associated with infection by CVA serotypes 4-7, 9, and 10; CVB serotypes 2 and 5; and EV71. The incubation time is 1-7 days.
  • A brief prodromal period is characterized by low-grade fever, malaise, abdominal pain, and/or respiratory symptoms.
  • Prominent historical features include oral pain and odynophagia, painless vesicles on the hands and feet, and a morbilliform eruption on the buttocks.
• Boston exanthem disease  
• • BED is caused by E16.
  • Similar to HFMD, BED begins with a brief febrile prodrome.
• Eruptive pseudoangiomatosis⁸  
• • EP is associated with E25 and E32.
  • An initial viral prodrome is characteristic.

Physical

• Herpangina
• • The enanthem is characterized by the presence of gray-white minute papulovesicles approximately 1-2 mm in diameter.
  • The lesions are surrounded by an erythematous halo, which progresses to a shallow ulcer covered by fibrin.
  • The lesions are self-limiting, resolving over 5-10 days.
  • Lesions are most frequently found on tonsils, uvula, soft palate, and anterior pillars of the tonsillar fauces.
  • The most important differential diagnosis to be considered is acute herpetic gingivostomatitis. However, acute gingivitis is not present in herpangina. Furthermore, herpetic gingivostomatitis is characterized by longer duration and more severe pain.
• Hand-foot-and-mouth disease
• • Oral lesions begin as erythematous macules and papules that are 2-8 mm in diameter; these progress to form thin-walled vesicles.
  • • The vesicles rapidly ulcerate, remaining as shallow painful ulcers surrounded by an erythematous halo.
    • Lesions heal without treatment over 5-10 days.
    • The lesions may be found anywhere in the oral cavity, but they most frequently appear on the hard palate, tongue, buccal mucosa, and gums.
    • The tongue may be erythematous and edematous, and pain may interfere with adequate oral intake.
  • Skin lesions are variably present, but they are characteristic when they occur.
  • • The lesions appear along with or shortly after the oral lesions appear, and they may vary in number from a few to more than 100.
    • They begin as erythematous macules or papules, which quickly become small (as large as 5 mm in diameter), gray, oval or linear vesicles surrounded by a red halo.
    • The hands are more commonly involved than the feet. Lesions usually occur on the lateral aspects of the fingers and toes, especially around the nails, but they may be seen in the digital flexures and on the palms and soles.
    • The lesions gradually disappear over 7-10 days, without scarring.
  • In some patients, especially infants, a more widespread papular or vesicular exanthem appears principally on the buttocks, although it may occasionally generalize.
  • In Asia, some epidemics of HFMD have been associated with severe refractory left ventricular failure, cardiogenic shock, CNS disorders, and death. These cases have generally been linked to EV71.
• Boston exanthem disease
• • After a brief febrile illness, pink macules and papules abruptly erupt on the face, trunk, and, less commonly, on the extremities.
  • Small ulcerations may be seen on the soft palate and tonsils.
• Eruptive pseudoangiomatosis
• • After the prodromal period, 2- to 4-mm blanchable, red papules resembling cherry angiomas appear.
  • The lesions usually number no more than 10, and they resolve spontaneously within 10 days.
  • They are distributed on the face, trunk, and extremities.
• Other associations
• • Acute hemorrhagic conjunctivitis^{9, 10, 2} is linked to EV70 and CVA24.
  • Pustular stomatitis associated with erythema multiforme is linked to CVB5.
  • Widespread vesicular eruption is linked to CVA4.
  • Gianotti-Crosti–like eruption is linked to CVA16.
  • Rubelliform eruption is linked to E2.
  • Morbilliform eruption is linked to E6, E11, and E25.
  • Rubelliform or morbilliform eruption is linked to E9.
  • Petechiae are linked to E11 and E19.
  • Punctate macular eruption is linked to E19.
  • Vesicular eruption is linked to E11.

Causes

See Pathophysiology.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

Enteroviral infections are diagnosed mainly on the basis of clinical features; however, a specific diagnosis of EV infection requires detection of the virus in patient samples. In some cases, complementary tests may be useful.

• Serologic studies
• • The detection of virus-specific IgM antibodies by means of enzyme-linked immunosorbent assay can aid diagnosis; however, because it is time-consuming to obtain results using this technique, it may be of limited value in a clinical setting.
  • Serum samples should be obtained during the acute phase of the disease because IgM antibodies rapidly disappear.
  • The antibodies are usually group specific and not type specific.
  • Serology has no role in routine diagnosis.
• Cell culture
• • Cell culture may allow isolation of the virus.
  • Samples may be obtained from the blood, stool, pharyngeal secretions, and vesicular fluid.
  • The most specific findings are found in samples from the blood and blister fluid. Findings in fecal specimens are least specific because EVs may be shed for weeks after acute infection and can be detected well after the clinical illness has resolved. A 2007 study revealed that a throat culture plus a culture of 2 sterile vesicles (or from the rectum if no sterile vesicles are present) may have the highest yield for detecting EV71 in persons with HFMD.¹¹
  • Although EVs take 4-8 days to grow and results are usually not available in sufficient time to impact treatment of the patient, culture remains an important epidemiologic tool. Viral culture allows the clinician to isolate and identify the serotype of the virus causing disease.
• Polymerase chain reaction
• • The reverse transcriptase polymerase chain reaction (PCR) has made enteroviral subtyping possible.
  • PCR techniques require small amounts of clinical material and are rapid (within 5-24 h of receipt of the sample), sensitive, and specific. It is superior to viral culture for the diagnosis of many EV infections, particularly enteroviral meningitis. Specimen sources are the same as those for cell cultures above.
  • Commercial EV PCR tests are available.
  • Because of their extreme sensitivity, PCR tests are subject to false-positive results due to contamination and to false-negative results due to levels below assay detection.
  • EV PCR provides the potential for a reduction in unnecessary hospitalization and diagnostic or therapeutic interventions.
  • PCR techniques are difficult and expensive and are not routinely performed.

Histologic Findings

In most cases, histopathologic findings are nonspecific and are not necessary for diagnosis.

When histopathologic examination is performed to evaluate HFMD, findings may include spongiosis, intraepidermal vesicles that contain neutrophils and mononuclear cells, and some necrotic keratinocytes. Edema and a perivascular infiltrate composed of lymphocytes and neutrophils may be seen in the dermis.

In EP, lesions are composed of dilated superficial vessels with plump endothelial cells. The lesions are easily distinguished from true angiomas because the number of vessels is not increased.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

Enteroviral infections heal spontaneously within 7-10 days; therefore, the main goal of treatment is symptomatic relief.

• Fever: Adequate hydration and antipyretics, such as acetaminophen, are helpful.
• Oral lesions
• • Mouth rinses with topical anesthetics (eg, lidocaine 2%) or antihistamines (eg, diphenhydramine hydrochloride) may relieve oral pain.
  • Acyclovir was used in an open clinical trial involving 13 patients with HFMD. Involution of oral lesions occurred within 24 hours of the start of therapy. The mechanism of action was unknown; to the authors’ knowledge, no other series results have been published.
  • Pleconaril is another antiviral drug that has demonstrated efficacy against EVs. It is a broad-spectrum antiviral drug that blocks enteroviral attachment to cellular receptors. Pleconaril therapy is prescribed for the treatment of some severe enteroviral infections, including meningoencephalitis and neonatal enteroviremia in immunosuppressed patients.¹²
  • Allopurinol mouthwashes (3 mg/mL) are reported to accelerate the resolution of oral lesions.¹³

FOLLOW-UP

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Complications

• EVs occasionally cause severe complications, especially cardiac and neurologic complications. These include the following:
• • Myocarditis
  • Aseptic meningitis: Nonpolio human EVs are the leading recognizable causes of aseptic meningitis, accounting for 80-92% of all cases in which a pathogen is identified.
  • Meningoencephalitis
  • Paralysis
• Coxsackievirus infections in pregnancy have been associated in several studies with increased rates of type 1 diabetes mellitus in the offspring. Additionally, maternal CVB infection during pregnancy may increase the rate of cardiac anomalies.¹⁴
• Enteroviral infection acquired during the first trimester of pregnancy may result in spontaneous abortion.

Prognosis

• In general, the systemic and cutaneous manifestations of EVs are self-limited. Cutaneous lesions heal without scarring.
• A few cases of prolonged or recurrent HFMD have been reported. In 1964, Evans and Waddington¹⁵ reviewed a large outbreak in South Wales. They described a relapsing course occurring over 2 years in one patient.

MISCELLANEOUS

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Enteroviral infections can be misdiagnosed as other viral infections such as herpes simplex or influenza.
• Enteroviral infection acquired during the first trimester of pregnancy may result in spontaneous abortion.

ACKNOWLEDGMENTS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Chad S Hendrickson, MD, and Alex Llambrich-Mañes, MD, to the development and writing of this article.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Erosions on the base of the tongue.
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Media file 2:  A red halo surrounds several vesicles on the finger flexures and palms.
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Media file 3:  Small linear vesicle on the thumb.
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Media file 4:  Vesicle on the dorsal hand of a young adult.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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Article Last Updated: Jun 20, 2008