Dermatologic Manifestations of Enteroviral Infections 

Updated: May 21, 2018
Author: Mercè Alsina-Gibert, MD; Chief Editor: Dirk M Elston, MD 

Overview

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] :

  • 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]
  • 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]
  • 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 enterovirus type D: These include enterovirus types 68, 70, 94, and 111. [2, 3]

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.

Erosions on the base of the tongue. Erosions on the base of the tongue.
A red halo surrounds several vesicles on the finge A red halo surrounds several vesicles on the finger flexures and palms.
Small linear vesicle on the thumb. Small linear vesicle on the thumb.
Vesicle on the dorsal hand of a young adult. Vesicle on the dorsal hand of a young adult.

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:

  • Prematurity
  • Maternal viral symptoms at delivery
  • Symptoms in the first week of life
  • 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.

 

Presentation

Physical Examination

Herpangina

The enanthem is characterized by the presence of gray-white small papulovesicles of approximately 1-2 mm in diameter and are most frequently found on the tonsils, uvula, soft palate, and anterior pillars of the tonsillar fauces.

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.

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 (HFMD)

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. 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. Scalp involvement with papules, crusts, and vesicles may also be present.[38, 39] Lesions heal without treatment over 5-10 days.

Skin lesions are variably present, but they are characteristic when they occur. They appear along with or shortly after the oral lesions, and they vary in number from a few to more than 100. They begin as erythematous macules or papules, which quickly become small (up to 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.

Atypical HFMD due to Coxsackie A virus (CVA) 16 and 6 has been described in both children and adults.[40, 41] In these cases, maculopapular rashes presenting on the hands, buttocks, or facial areas, with or without vesicles or bullae on any sites of the body, can occur.[36, 42] Oral involvement includes petechiae, strawberry tongue, and enanthem, but in about 40% of cases there are no mucosal lesions.[43]

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 (BED)

After a brief febrile illness, pink macules and papules abruptly erupt on the face, upper trunk, and, less commonly, on the extremities.

Small ulcerations may be seen on the soft palate and tonsils.

Eruptive pseudoangiomatosis (EP)

After the prodromal period, 2-4 mm blanchable, red papules resembling cherry angiomas appear.

The lesions usually number no more than 10, and they resolve spontaneously within a few weeks.

They are distributed on the face, trunk, and extremities.

Complications

Enteroviruses can cause severe complications, especially cardiac and neurologic complications. These include the following:

  • Myocarditis
  • Aseptic meningitis: Nonpolio human enteroviruses are the leading recognizable causes of aseptic meningitis, accounting for 80-92% of all cases in which a pathogen is identified. Certain enteroviruses (eg, coxsackie B virus [CVB] 5; echoviruses 6, 9, and 30) are more likely to cause meningitis outbreaks, while others (coxsackie A virus [CVA] 9, CVBs 3 and 4) are the cause of endemic aseptic meningitis. [44]
  • Meningoencephalitis, which can be chronic in immunocompromised patients.
  • Sepsis [45]
  • Hepatitis
  • Disseminated intravascular coagulation
  • Pancreatitis [46]
  • Acute flaccid myelitis linked to enterovirus D68 [47]
  • Debut of type 1 diabetes mellitus reported after enteroviral infection [48]

A case-control study of 553 cases of severe hand-foot-mouth disease (HFMD) identified enterovirus 71 (EV71), convulsion, dyspnea, and vomiting as risk factors for death.[49]

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,[50] while enteroviral infection acquired during the first trimester of pregnancy may result in spontaneous abortion.

 

DDx

Diagnostic Considerations

Clinical diagnosis of dermatological manifestation of enteroviral infections is based on epidemiology, clinical history and physical examination.  For mild cases, specific enteroviral serotype diagnosis is useful for surveillance but does not change management. 

Differential Diagnoses

 

Workup

Laboratory Studies

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

Serologic studies

The detection of virus-specific immunoglobulin M (IgM) antibodies by means of enzyme-linked immunosorbent assay (ELISA) can aid diagnosis and can be detected as early as the second day of infection.

Serum samples should be obtained during the acute phase of the disease since IgM antibodies rapidly disappear. The antibodies are usually group specific and not serotype specific.

No universal antibody or antigen assay exists because no single antigen is present in all enterovirus serotypes. Serology has no role in routine diagnosis.

Cell culture

Cell culture may allow isolation of the virus. Samples are obtained from the blood, stool, pharyngeal secretions, or vesicular fluid. Some reports suggest that the best results are achieved when samples are collected from the upper respiratory tract, gastrointestinal tract, or cerebrospinal fluid. However, the most specific findings are found in samples from blood and blister fluid. Findings in fecal specimens are least specific because enteroviruses 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 two sterile vesicles (or from the rectum if no sterile vesicles are present) may have the highest yield for detecting enterovirus 71 (EV71) in patients with hand-foot-and-mouth disease (HFMD).[51]

Although enteroviruses take 4-8 days to grow and results are not usually available in sufficient time to have an impact on 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 (RT-PCR) has made enteroviral subtyping possible and has increased the enterovirus detection rate, especially in the analysis of cerebrospinal fluid.

As a reaction to the August, 2014 enterovirus D68 outbreak in the United States, the CDC has developed and begun using a new and faster laboratory test for enterovirus D68.[52] With RT-PCR testing, new outbreaks can be identified within a few days, rather than the weeks it took previously.

RT-PCR assays permit shorter turnover times, especially for the detection of enterovirus RNA.[53]

PCR techniques require small amounts of clinical material and are rapid (within 5-24 h of receipt of the sample), sensitive, and specific. PCR is superior to viral culture for the diagnosis of many enterovirus infections, particularly enteroviral meningitis.[54] Specimen sources are the same as those for cell cultures, as outlined above.

Because of their extreme sensitivity, these tests are subject to false-positive results due to contamination and to false-negative results due to levels below assay detection.

RT-PCR provides the potential for a reduction in unnecessary hospitalization and diagnostic or therapeutic interventions.

New techniques such as rapid polymerase recombinase polymerase amplification assay for coxsackie A6 have extremely high sensitivity and specificity and may be useful in public health control and outbreak notification.[55]

Histologic Findings

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

When a skin biopsy is performed to evaluate hand-foot-mouth disease (HFMD), findings may include spongiosis, intraepidermal vesicles that contain neutrophils and mononuclear cells, and some necrotic keratinocytes.[56, 57, 58] Edema and a perivascular infiltrate composed of lymphocytes and neutrophils may be seen in the dermis. Atypical forms of HFMD caused by coxsackie A6, mainly occurring in adults, show neutrophil-rich infiltrates with involvement of the stratum granulosum and spinosum.[40] Keratinocyte necrosis and vacuolization of the basal membrane may also be found. Adnexal structures can also be involved with neutrophil infiltrates.[41]

In eruptive pseudoangiomatosis (EP), lesions are composed of dilated superficial vessels with plump endothelial cells and mild lymphocytic infiltrate. The lesions are easily distinguished from true angiomas since there is no increase in the number of vessels.

Other Tests

There are no clear biomarkers. However, High levels of serum acetylcholinesterase were seen in a large cohort of Chinese patients with hand-foot-mouth disease (HFMD) caused by enterovirus 71 (EV71).[59]

 

Treatment

Medical Care

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

Neonates show a wide spectrum of signs and symptoms, which range from a nonspecific febrile illness to potentially fatal multisystem disease.[2]

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.[60]

Acyclovir was used in an open clinical trial involving 13 patients with hand-foot-and-mouth disease (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.

Allopurinol mouthwashes (3 mg/mL) are reported to accelerate the resolution of oral lesions.

Immunoglobulin

Some anecdotal evidence suggests that prophylactic immunoglobulin can mitigate disease severity in some exposed neonates. Immunoglobulin has also been used for the treatment of symptomatic infants with enterovirus infection.[2]

Pleconaril

This antiviral drug has demonstrated efficacy against enteroviruses. It is a broad-spectrum antiviral drug that blocks enteroviral attachment to cellular receptors.[61, 62, 63] Pleconaril therapy is prescribed for the treatment of severe neonatal enteroviral sepsis.[64] A randomized controlled trial conducted in neonates with enteroviral sepsis showed a shorter time to negativity and a greater survival at 2 months in the pleconaril group.[65]

Pyridyl imidazolidinone

A novel class of capsid binder, pyridyl imidazolidinone can inhibit enterovirus 71 (EV71) replication.[1]

Other treatments

Direct-acting antivirals targeting capsid entry, RNA polymerase, ATPase, cyclophilins, and assembly inhibitors and protease inhibitors are being evaluated.[66] However, to date there is no adequate treatment.

Pirodavir, pocapavir and vapendavir are capsid inhibitors that have shown effectiveness in phase 2 clinical trials.[67]

Some other repurposed drugs seem to be effective in animals, such as ribavirin and itraconazole.[67, 68] Idarubicin has also been shown to be an enterovirus replication inhibitor.[69]

Prevention

Adequate hand hygiene of contacts prevents the spread of disease. Alcohol-based solutions may not completely eradicate viral particles. 

Vaccination

Development of an inactivated enterovirus vaccine[70] and an inactivated whole virus–based bivalent vaccine for both enterovirus 71 (EV71) and coxsackie A virus (CVA) 16 is in progress.[71] A vaccination program for enterovirus E71 in China seems to be cost-effective in preventing morbidity and mortality.[72] In a 2017 review of all available vaccines for E71, the highest effectivity was of 80% in severe cases of hand-foot-mouth disease (HFMD). It should be taken into account that HFMD may be caused by several enteroviruses.[73] Therefore, a monovalent vaccine would only protect against other serotypes if cross-reactions immunogenicity were present.