eMedicine Specialties > Dermatology > Viral Infections

Enteroviral Infections

Author: Susanna Nogués-Siuraneta, MD, Resident, Department of Dermatology, Hospital Clinic de Barcelona
Coauthor(s): Mercè Alsina-Gibert, MD, Consultant, Department of Dermatology, Hospital Clinic, Spain; Steven Brett Sloan, MD, Assistant Professor, Department of Dermatology, University of Connecticut School of Medicine; Director of Nail Disease Clinic and Chief of Dermatology, Newington Veterans Affairs Medical Center
Contributor Information and Disclosures

Updated: Jun 20, 2008

Introduction

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

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.

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