Background
The human enterovirus genus is a member of the Picornaviridae family of small, icosahedral, single-stranded, positive-sense RNA viruses. More than 100 serotypes are currently recognized by the International Committee on Taxonomy of Viruses, and are classified in four groups according to the RNA of the structural protein VP1, as follows [1] :
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Human enterovirus type A (20 serotypes): These include coxsackie A virus types 2-8, 10, 12, 14, 16 and enterovirus types 71, 76, 89-92, 114, 119-121. [2]
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Human enterovirus type B (61 serotypes): These include coxsackie A virus type 9; coxsackie B virus types 1-6; echovirus types 1-7, 9, 11-21, 24-27, 29-33; and enterovirus types 69, 73-76, 77-88, 93, 97, 98, 100, 101, 106, and 107. [2]
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Human enterovirus type C (16 serotypes): The most well known are coxsackie A virus types 1, 11, 13, 15, 17, 19-22, and 24. Human enterovirus types 95, 96, 99, 102, 104, 105, 109, 116, and 118 and poliovirus types 1-3 have been included in this group. [2]
Human enteroviruses are distributed worldwide, with two major patterns of infections within a given geographical area: endemic and epidemic. [1]
Enteroviruses usually cause transient, often subclinical, infections. They are responsible for a wide variety of syndromes, including exanthematous fever, enteritis, encephalitis, aseptic meningitis, myocarditis, and respiratory tract infections. Coxsackieviruses, echoviruses, and enterovirus type 71 are also significant causes of cutaneous disease. Enteroviruses cause outbreaks that range from small, community clusters due to acute hemorrhagic conjunctivitis, to large nationwide human enterovirus 71 epidemics. [2] A relationship between enterovirus' RNA and chronic fatigue syndrome has been described. [4] These viruses could initiate and perpetuate the immunological response seen in chronic fatigue syndrome.
Coxsackieviruses are divided into two groups, A and B. Group A consists of 23 serotypes (1-22, 24) and group B consists of six serotypes (1-6). Coxsackie A viruses (CVAs) are the primary etiologic agents of herpangina and hand-foot-and-mouth disease (HFMD). Coxsackie B viruses (CVBs) are associated with epidemic pleurodynia (ie, Bornholm disease), epidemic myalgia, myocarditis, and pericarditis. Bowles et al suggested that CVB may be an etiologic agent of juvenile dermatomyositis. [5]
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 al first isolated the CVA 16 serotype in 1957 during a Canadian epidemic of exanthema and stomatitis. [6] Two years later, Alsop et al used the term hand-foot-and-mouth disease to describe a similar eruption in England. [7]
Echoviruses include 34 distinct serotypes, and at least half can cause a rash. The two skin diseases specifically associated with echoviruses are Boston exanthem disease (BED), caused by echovirus type 16, and eruptive pseudoangiomatosis, (EP) caused by echovirus types 25 and 32.
Pathophysiology
Enteroviruses spread from person to person by either oral-oral or fecal-oral routes. The viral particles can be isolated from cutaneous and ocular lesions and, therefore, may also be transmitted through direct contact with fluid from these lesions. Virus shedding could also be disseminated by fomites such as objects in a pediatric office. [8] Similarly, nosocomial infection of enteroviruses in neonatal intensive care units has been described. [9]
Aerial transmission is another important route by which enterovirus D68 and other serotypes cause respiratory illness. [10, 11] Airborne virus particles have been isolated in respiratory inhaled droplets. [12] Moreover, enteroviruses are easily detectable in natural and treated water sources such as swimming pools or water for consumption. [13]
It has been suggested that enteroviruses can be transmitted antenatally, either transplacentally or potentially via ascending infection. When maternal enterovirus infection is acquired during late pregnancy, vertical transmission has been shown to be relatively common. [2]
These infectious agents are highly contagious, and are a common cause of widespread outbreaks. After the ingestion of infectious particles, enteroviruses 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. Viruses may also disseminate by hematogenous spread, which results in a more severe and characteristically systemic disease.
Immune activation by the enterovirus 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 they do so in different patterns, based on country, serotype, and specific population, making comparisons of disease-based studies among these groups difficult.
Etiology
Coxsackieviruses and echoviruses 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. Note the images below.
Seasonal distribution is a characteristic feature. In temperate climates, enteroviral infections are more common in the summer and autumn, whereas in tropical areas, they tend to occur year round. The most characteristic clinical syndromes caused by enteroviruses are described below.
Herpangina
The main cause is coxsackie A virus (CVA) (serotypes 2-6, 8, and 10). Other viral etiologies include coxsackie B viruses (CVB) (serotypes 1-4), echoviruses, adenoviruses, and other enteroviruses. [14, 15] 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. See Herpangina for more detailed information.
Hand-foot-and-mouth disease (HFMD)
HFMD is most commonly associated with CVA 16, but also with infection by CVA serotypes 4-7, 9, 10, and 24; CVB serotypes 2 and 5; echoviruses 1, 4, 11, and 18; and human enterovirus 18. In Asian countries, enterovirus 71 (EV71) is one of the most common causes of HFMD. [2] Since 2008, CVA 2 has been reported as a cause of HFMD in China. [16] In the last decade, outbreaks of an atypical and more severe form of HFMD affecting both children and adults have been reported, mainly caused by CVA 6. The new spread seems to be related to new recombination groups. [17]
The incubation time is 1-7 days. [15, 18] A brief prodromal period is characterized by low-grade fever, malaise, abdominal pain, lymphadenopathy, and/or respiratory symptoms. After 24-48 hours, vesicles appear on buccal mucosa and the tongue, associated with oral pain and odynophagia. Painless papules and vesicles on the hands, feet, and some other parts of the body and a morbilliform eruption on the buttocks can also be seen. The oral enanthem helps to distinguish HFMD from other viral causes. Uncomplicated HFMD usually resolves in 5-7 days. [19]
HFMD due to EV71 might cause severe neurological manifestations, including poliolike paralysis, brainstem encephalitis, and fatal cardiopulmonary complications with or without HFMD. [3] Recurrent episodes affect up to 4% in the subsequent 3 years. [20]
See Hand-Foot-Mouth Disease for more information.
Boston exanthem disease (BED)
BED is caused by echovirus 16. As with HFMD, BED begins with a brief febrile prodrome.
Eruptive pseudoangiomatosis (EP)
EP is associated with echovirus 25 and echovirus 32. An initial viral prodrome is characteristic. [21]
Eczema coxsackium
A vesicular eruption on traumatized or inflamed skin similar to eczema herpeticum but caused by CVA 16 and 6 has been reported. [22]
Other associations
Acute hemorrhagic conjunctivitis [23, 24, 25] is linked to enterovirus 70 and CVA 24.
Pustular stomatitis associated with erythema multiforme is linked to CVB 5. [26]
Widespread vesicular eruption is linked to CVA 4.
Gianotti-Crosti–like eruption is linked to CVA 16.
Rubelliform eruption is linked to echovirus 2.
Morbilliform eruption is linked to echoviruses 6, 11, and 25.
Rubelliform or morbilliform eruption is linked to echovirus 9.
Petechiae are linked to echoviruses 11 and 19.
Punctate macular eruption is linked to echovirus 19.
Vesicular eruption is linked to echovirus 11.
Some epidemiological studies strongly suggest that coxsackievirus infections, in particular type B coxsackieviruses, are related to the induction or exacerbation of type 1 diabetes. [27, 28]
Epidemiology
United States
Although enteroviruses are responsible for an estimated 50 million infections and 30,000-50,000 hospitalizations each year, it is notable that less than 1% of infections result in significant symptomatic illness and the vast majority of hospitalizations are for aseptic meningitis. [29]
The US Centers for Disease Control and Prevention (CDC) reported an outbreak of enterovirus 68 from mid August 2014 to January 15, 2015 and a total of 1,153 people in 49 states were affected. [30] However, between January 2015 and June 2016, the number of confirmed new cases fell abruptly: to zero in 2015 and to four cases as of June 3, 2016. [30]
International
Although the frequency of enteroviral infection is not known, a sentinel surveillance system was established at the Taiwan Center for Disease Control (CDC, Taiwan) in 1998 to assess the epidemiologic features of enterovirus type 71 (EV71) infection. It registered 1,571 severe cases of hand-foot-mouth disease/herpangina from 1998-2007. [19]
In 2012 in Cambodia, a fatal outbreak of EV71 affecting children aged younger than 3 years with neurological and respiratory involvement resulted in 56 deaths in 61 cases reported. [31] In China, a total of 852,925 cases of hand-foot-mouth disease (HFMD), including 77 deaths, were reported as of May 31, 2016. [32] The estimated annual incidence of HFMD was 384.31 cases per 100,000 and less than 0.5% were severe. [33]
The overall number has been estimated at 1 billion or more annually worldwide.
Season
Enteroviral infections are more frequent in summer and early fall, but may occur at any time of year. [34, 35]
Sex
A male predominance has been observed in several epidemiological studies. [35, 36]
Age
Infants are highly susceptible to enteroviruses. Enteroviral infections mainly affect children younger than 5 years, probably because they lack cross-reacting immunity resulting from repeated exposure, but they are not uncommon in adults. [35]
Prognosis
In general, the systemic and cutaneous manifestations of enteroviruses in immunocompetent individuals are self-limited. Cutaneous lesions heal without scarring. Mortality rates range from 0-42% in the neonatal period. Risk factors for severe infection are as follows:
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Prematurity
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Maternal viral symptoms at delivery
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Symptoms in the first week of life
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No specific antibodies (acquired by placental transfer) of the infecting serotype in the neonate [2]
A few cases of prolonged or recurrent hand-foot-mouth disease (HFMD) have been reported. In 1964, Evans and Waddington [37] reviewed a large outbreak in South Wales and already described a relapsing course occurring over 2 years in one patient.
Some evidence suggests that enterovirus 71 CNS involvement can cause not only acute and severe complications with higher mortality, but also long-term neurologic and psychiatric disorders. [19] Occasionally, cardiac complications occur, leading to fulminant myocarditis and death in neonates. Deaths in neonates infected with enteroviruses have been reported and are usually the result of fulminant myocarditis.
When viral transmission is antenatal, neonatal enterovirus infection is very severe and has a poor outcome. [2]
Patient Education
Propper hand washing is recommended in people in contact with an enteroviral infection in order to decrease disease transmission.
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Erosions on the base of the tongue.
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A red halo surrounds several vesicles on the finger flexures and palms.
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Small linear vesicle on the thumb.
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Vesicle on the dorsal hand of a young adult.
