Dermatologic Manifestations of Hand-Foot-and-Mouth Disease

Hand-foot-and-mouth disease (HFMD) is a viral illness with a distinct clinical presentation of oral and characteristic distal extremity lesions. Most commonly, the etiologic agents are coxsackieviruses, members of the Picornaviridae family.

Epidemic hand-foot-and-mouth disease (HFMD) viral infections are usually caused by members of the Enterovirus genus, most commonly, coxsackievirus A16, A6, or enterovirus 71. In addition, sporadic cases with coxsackievirus types A4-A7, A9, A10, B1-B3, and B5 have been reported. Infections usually occur as isolated events, but epidemics occur regularly. An outbreak of HFMD in China during 2003 was caused by echovirus 19.[1] More widespread involvement resembling eczema herpeticum, systemic involvement, and late-stage onychomadesis are characteristic of the A6 strain.

Large outbreaks of HFMD in China in recent years have shown that increasing numbers of outbreaks are caused predominantly by enterovirus 71 (86.5%), and in part by coxsackievirus A16 (6.9%). The high incidence of mixed infections with enterovirus 71 and coxsackievirus 16 (17.6% of the total coxsackievirus 16–infected cases) has never before been observed in China.[2] A high incidence of mixed infections with enterovirus 71 and coxsackievirus 16 was also observed.[3] Enterovirus 71 infection does not provide immunity to other strains.[4]

The incubation period averages 3-6 days. Coxsackievirus infection is highly contagious. During epidemics, the virus is spread by horizontal transmission from child to child and from mother to fetus. Transmission occurs by means of direct contact with nasal and/or oral secretions, fecal material, or aerosolized droplets in a fecal-oral or oral-oral route. Initial viral implantation in the buccal and ileal mucosa is followed by spread to lymph nodes within 24 hours. Viremia rapidly ensues, with spread to the oral mucosa and skin. By day 7, neutralizing antibody levels increase and the virus is eliminated.

However, a study from China in 2011 showed that the neutralizing antibody response was not correlated with disease severity, suggesting that cellular immune response, besides neutralizing antibodies, could play a critical role in controlling the outcome of enterovirus 71 infection in humans.[5]

Epidemic hand-foot-and-mouth disease (HFMD) infections are usually caused by coxsackievirus A16 or enterovirus 71.[6] In addition, sporadic cases with coxsackievirus types A4-A7, A9, A10, B1-B3, and B5 are reported. An outbreak of hand-foot-and-mouth disease in China during 2003 was caused by echovirus 19.[1]

An outbreak in Taiwan caused by coxsackievirus A6 showed patients with atypical HFMD presentations in which the patients presented with widespread, blistering mucocutaneous reactions mimicking a severe drug reaction or Stevens-Johnson syndrome.[7]

An additional outbreak in the United States in 2011-2102 also caused by coxsackievirus A6 again showed atypical HFMD presentations in which the patients presented with a vesiculobullous and erosive eruption involving more than 10% of the body surface area.[8]

Frequency

United States

Hand-foot-and-mouth disease (HFMD) epidemics tend to occur every 3 years in the United States.

International

Worldwide HFMD occurrences are reported. A seasonal pattern is present in temperate climates, with a peak incidence in late summer and early fall.

Race

No racial predilection is recognized for hand-foot-and-mouth disease.

Sex

The male-to-female ratio for hand-foot-and-mouth disease is 1:1. Recent large outbreaks of HFMD in China have shown a male-to-female ratio closer to 1.5:1.[9]

Age

Most cases of hand-foot-and-mouth disease affect children younger than 10 years, although cases in adults are reported. Recent large outbreaks of HFMD in China have shown that 95% on infections occur in children younger than 5 years.[9]

The prognosis for hand-foot-and-mouth disease (HFMD) is excellent; except in large epidemics caused by human enterovirus 71 in which neurologic complications and death have been reported, especially in children.

HFMD is more severe in infants and children than adults, but generally, the disease has a mild course. Coxsackie A6 often presents with more generalized involvement, as well as with more severe systemic symptoms.[10]

Enteroviral infections may also cause myocarditis, epididymitis, pneumonia, meningoencephalitis, and even death.[11] MicroRNA profiles and elevated circulating histones have been used to characterize more severe disease.[12, 13]

Rarely, disease recurs.

Infection in the first trimester may lead to spontaneous abortion or intrauterine growth retardation.

A large outbreak of HFMD in Taiwan caused by enterovirus 71 had a high mortality rate of 19.3% in the severe cases; the deaths resulted from pulmonary hemorrhage. During this outbreak, mortality rates were highest in children younger than 3 years.[14]

In a large epidemic (138 cases) of HFMD related to enterovirus 71 in Singapore, 7 fatalities occurred, most from interstitial pneumonitis or brainstem encephalitis. The report's conclusions were that in general, HFMD is a benign disease but the presence of unusual physical findings, elevated total white blood cell count, and vomiting and the absence of oral ulcers may signify a patient with higher risk of a fatal outcome.[15] Newer reports of large outbreaks of HFMD in China have shown that longer duration of fever, elevated serum C-reactive protein (CRP), and hyperglycemia are risk factors for increased severity of disease.[9]

A later study of an HFMD epidemic (14 children) in Australia, again with enterovirus 71, reported that 9 (64%) developed severe neurologic disease in which the host immune response seemed to cause most of the neurologic manifestations.[16]

In one study of an outbreak HFMD in Sarawak, Malaysia caused by human enterovirus 71, the authors identified 3 clinical risk factors to help detect children at risk for neurologic complications. Total duration of fever for 3 or more days, peak temperature elevation greater or equal to 38.5°C, and a history of lethargy all were independently associated with cerebrospinal fluid pleocytosis and neurologic disease.[17]

In an outbreak in the Republic of Korea with enterovirus 71, duration of fever longer than 4 days, peak temperature elevation greater than 39°C, vomiting, headache, neurologic signs, and serum glucose value over 100 mg/dL were all significant risk factors for neurologic complications.[18]

The virus that causes hand-foot-and-mouth disease (HFMD) may be present in the patient's stool for 1 month.

The patient’s exclusion from school is generally not required.

Good hand-washing technique is necessary to reduce the potential spread of disease.

To reduce viral spreading, do no rupture blisters.

A brief prodrome of 12-36 hours duration is part of the usual presentation of hand-foot-and-mouth disease (HFMD), which consists of the following:

• Low-grade fever with an average temperature of 38.3°C and duration of 2-3 days

• Anorexia

• Malaise

• Abdominal pain

• Sore mouth

• Cough

In one study, 80% of the children presented with anorexia and mouth soreness. The enanthem usually precedes the exanthem that is asymptomatic, but both may occur simultaneously. The lesions on the hands and feet are present for 5-10 days. The mucosal and cutaneous lesions heal spontaneously in 5-7 days.

Hand-foot-and-mouth disease (HFMD) is more severe in infants and children than adults, but generally, the disease has a mild course. Symptoms such as malaise, low-grade fever, and anorexia are often present. Occasionally, patients have high fever, marked malaise, diarrhea, and arthralgias.

Enteroviral infections may also cause myocarditis, pneumonia, meningoencephalitis, and even death. Infection in the first trimester may lead to spontaneous abortion or intrauterine growth retardation.

Rarely, disease recurs. One report describes a 15-year-old white boy with recurrent episodes of HFMD at 3 weeks and 7 months following the initial viral illness.[19] The lesions in the recurrent episodes were located in the same distribution as the initial presentation. His workup after the last case revealed an absence of immunodeficiency and a greater than 4-fold increase in coxsackievirus B titers. No serologic evidence of acute infection was identified, and titers of immunoglobulin G remained elevated for 1 year following this third episode.

Oral lesions begin as erythematous macules that evolve into 2-3 mm vesicles on an erythematous base. The vesicles are rarely observed because they rapidly become ulcerated. They are painful and may interfere with eating. The total number of ulcers averages 5-10. The vesicles may involve the palate, buccal mucosa, gingiva, and tongue. The tongue is involved in 44% of the cases, and, in addition to the ulcers, the tongue may be edematous and tender. Note the images below.

The lower lip has an ulcer with an erythematous halo.

The tongue has an ulcer with an erythematous halo.

Cutaneous lesions are characteristic and are present in two-thirds of patients. Typically, the hands, feet, and buttocks are involved. The hands are involved more often than the feet, and the dorsal aspect of the hands and sides of the fingers are more commonly involved than the palmar surfaces. Each lesion begins as a 2-10 mm erythematous macule on which a central, gray, oval vesicle develops. The lesions are characteristically elliptical; their long axis parallels the skin lines. These lesions are asymptomatic and resolve in 3-7 days as a result of fluid resorption. Note the image below. Erythematous maculopapular eruptions may also occur on the buttocks and arms. In one report, 22% of the patients also had marked cervical or submandibular lymphadenopathy.

More recently, in large outbreaks of HFMD related to coxsackievirus A6 infection, patients experienced more widespread lesions, sometimes resembling eczema herpeticum; more severe systemic symptoms; larger blisters; and late-stage onychomadesis, skin peeling, and desquamation of palms and soles.[20] See the image below.

A typical cutaneous lesion has an elliptical vesicle surrounded by an erythematous halo. The long axis of the lesion is oriented along the skin lines.

A recent outbreak in Taiwan caused by coxsackievirus A6 showed patients with atypical HFMD presentations in which the patients presented with widespread, blistering mucocutaneous reactions mimicking a severe drug reaction or Stevens-Johnson syndrome.[7]

An additional outbreak in the United States in 2011-2102 also caused by coxsackievirus A6 again showed atypical HFMD presentations in which the patients presented with a vesiculobullous and erosive eruption involving more than 10% of the body surface area. This was perioral, extremity, and truncal in addition to typical hand, foot, and mouth locations. In addition, in 55% of patients, the eruption was accentuated in areas of prior eczematous dermatitis, "eczema coxsackium." Gianotti-Crosti–like (37%) and petechial/purpuric (17%) eruptions were also seen.[8]

Dehydration occasionally occurs in children with hand-foot-and-mouth disease (HFMD).

Rarely, complications of hand-foot-and-mouth disease include meningoencephalitis, myocarditis, pulmonary edema, and death.

Desquamation of palms and soles and onychomadesis may develop after the infection.[20]

A case report in 2105 reported an adult with concurrent HFMD who also developed acute unilateral maculopathy. Empirical treatment with oral corticosteroids was commenced and the inflammation resolved, leaving a residual macular scar.[21]

Generally, no laboratory studies are necessary for hand-foot-and-mouth disease (HFMD). Leukocyte counts are 4000-16,000/µL. Occasionally, atypical lymphocytes are present.

Recent studies show that elevated serum concentration of C-reactive protein (CRP) and fasting and elevated blood glucose were significantly higher in severe cases than in mild ones.[9]

The virus can be isolated from swabs of the vesicles or mucosal surfaces or from stool specimens and then inoculated into mice or cultured on viral tissue media.

Neutralizing antibodies rapidly disappear; thus, they are usually detectable only in the acute phase.

High levels of complement-fixing antibodies are present in the convalescent phase.

Studies have illustrated the usefulness of a molecular assay using polymerase chain reaction primers to arrive at a rapid and specific diagnosis in order to distinguish between coxsackievirus A16 and enterovirus 71.[22] This may hold promise in future outbreaks because infections with enterovirus 71 tend to be associated with more severe complications and fatalities. One study suggests that swabs be collected within 4 days of HFMD onset to increase diagnostic yield.[23]

A 2020 study showed promising results for effective early noninvasive diagnosis of enterovirus A71 infection in children using saliva swabs, with detection of IgA-specific antibodies to enterovirus A71.[24]

Acute flaccid paralysis associated with enterovirus 71–infected hand-foot-and-mouth disease (HFMD) can be seen in severe cases. MRI is an effective modality to investigate neurological complications associated with the enterovirus 71 epidemics. Involvement of posterior portions of the medulla oblongata and pons, and bilateral anterior horns of the spinal cord, are characteristic findings.[25]

Classic histopathologic findings of hand-foot-and-mouth disease (HFMD) include an intra-epidermal vesicle that contains neutrophils and eosinophilic cellular debris. The adjacent epidermis has reticular degeneration, that is, intercellular and intracellular edema. The dermis has a mixed infiltrate. Eosinophilic intranuclear inclusions are observed with electron microscopic studies.

Neuropathology in fatal cases of enterovirus 71 infection have shown features of an acute encephalitis involving the brain stem and spinal cord.[26]

Usually, no medical care is necessary for hand-foot-and-mouth disease (HFMD), as most cases are mild. Exceptions include some serious complications from enterovirus 71 infections. Vaccines are in development and being matched to prevalent strains.[27, 28]

Research from China in 2012 shows that geraniin, a form of a tannin separated from the geranium plant, effectively inhibited virus replication in rhabdomyosarcoma cells with an IC50 (concentration that inhibits 50%) of 10 μg/mL. Moreover, geraniin treatment of mice that were challenged with a lethal dose of enterovirus 71 resulted in a reduction of mortality, relieved clinical symptoms, and inhibited virus replication in muscle tissues. The results suggest that geraniin may be used as a potential drug for treatment of enterovirus 71 infection.[29]

Research also shows lycorine may be a potential drug candidate for the clinical treatment of enterovirus 71–infected patients. Lycorine treatment of mice challenged with a lethal dose of enterovirus 71 resulted in reduction of mortality, clinical scores, and pathological changes in the muscles of mice, which were achieved through inhibition of viral replication. When mice were infected with a moderate dose of enterovirus 71, lycorine treatment was able to protect them from paralysis.[30]

Topical disinfectants show varied ability to inactivate the virus to prevent transmission.[31]

A case report of severe HFMD from enterovirus infection in an immunocompromised patient described a faster resolution of symptoms and lesions with oral acyclovir.[32]

Low-level laser therapy has also been shown to shorten the duration of painful oral ulcers.[33]

Outpatient care

For symptomatic pain control for oral ulcers associated with HFMD, elixirs such as diphenhydramine (Benadryl), aluminum and magnesium hydroxide (Mylanta), and sucralfate (Carafate) can be helpful. Several times daily, the patient should swish the elixir in his or her mouth and spit it out.

The application of topical viscous lidocaine with a cotton-tipped swab several times daily can help in controlling the pain caused by oral ulcers.

Studies from China have shown that most of the children with hand-foot-and-mouth disease (HFMD) presented with vitamin A insufficiency, which was associated with their reduced immunity and more severe illness.[34]

Studies of large outbreaks of childhood HFMD in China have shown that risk factors for HFMD included playing with neighborhood children, visiting an outpatient medical clinic for another reason, and community exposures to crowded places. In this study, good hand-washing techniques by preschool-aged children and their caregivers had a significant protective effect against community-acquired HFMD from human enterovirus 71 infection.[35]

In a study of a large pediatric outbreak due to enterovirus 71 in China, several factors were studied to see which were predictive of increased severity in HFMD. Prior Epstein-Barr virus exposure, enterovirus 71 infection, and rural residence were associated with severe infections, while breastfeeding was a protective factor.[36]

Topical disinfectants show varied ability to inactivate the virus to prevent transmission.[31]  

On December 3, 2015, the China Food and Drug Administration approved the first inactivated enterovirus 71 whole virus vaccine for prevention of severe HFMD. However, it is still not widely available commercially worldwide.[37]

A study in 2015, looking at disinfectants to halt the spread of HFMD viruses, tested 13 commercially available products. The results showed acidic ethanol disinfectants, alkaline cleaners, and sodium hypochlorite were very effective. Neutral ethanol disinfectants, hand soaps, and quaternary ammonium compound sanitizers did not show great effect against HFMD viruses.[38]

In 2020, a report from China demonstrated the clinical (real-world) effectiveness of three vaccines against enterovirus A71 in prevention of severe HFMD.[39] The risk of for enterovirus A71 infection in children aged 6-36 months was reduced by use of the vaccine. The inactivated vaccines performed well in severe HFMD.

The topical application of anesthetics is beneficial. Viscous lidocaine, dyclonine solution, or diphenhydramine (Benadryl) may be used to treat painful oral ulcers. Antipyretics may be used to manage fever, and analgesics may be used to treat arthralgias.

Class Summary

These agents provide symptomatic relief of pain as a result of mucosal lesions.

Dyclonine (Dyclone)

Dyclonine is a topical anesthetic available in a solution, spray, or lozenge. It affects cell membrane permeability and blocks impulses at peripheral nerve endings in the skin.

Lidocaine topical (AneCream, AneCream5, Derma Numb)

Viscous lidocaine is a topical anesthetic. It decreases permeability to sodium ions in neuronal membranes and results in inhibition of depolarization, blocking the transmission of nerve impulses.

Class Summary

Antihistamines act by means of the competitive inhibition of histamine at the H1 receptor. This effect mediates wheal and flare reactions, bronchial constriction, mucous secretion, smooth muscle contraction, edema, hypotension, CNS depression, and cardiac arrhythmias.

Diphenhydramine (Benadryl, Benylin, Diphen, AllerMax)

Diphenhydramine is in the ethanolamine class, a histamine receptor type 1 blocker. It has significant anticholinergic and sedative properties that causes some degree of topical anesthesia by impairing the transmission of nerve impulses.

Class Summary

These agents are used for the symptomatic treatment of acid-induced gastritis and the treatment of GI ulcers.

Sucralfate (Carafate)

Sucralfate is an aluminum complex antacid that may help in the treatment of oral mucosal ulcerations. Similar to its effects on GI ulcers, sucralfate forms a viscous adhesive substance that protects the GI lining against pepsin, peptic acid, and bile salts. It binds and covers the ulcer, promoting healing.

Aluminum hydroxide, magnesium hydroxide, simethicone (Mylanta)

The combination of aluminum hydroxide, magnesium hydroxide, and simethicone lowers gastric pH and covers ulcer bases. Similar to its effect on GI ulcers, it may cover the ulcer base, allowing more rapid healing. Magnesium and/or aluminum antacid mixtures are used to prevent bowel function changes.