Hand-Foot-and-Mouth Disease (HFMD)


Practice Essentials

Hand-foot-and-mouth disease (HFMD) is an acute viral illness that presents as a vesicular eruption in the mouth (see the image below), but it can also involve the hands, feet, buttocks, and/or genitalia. Coxsackievirus A type 16 (CVA16) is the etiologic agent involved in most cases of HFMD, but the illness is also associated with coxsackievirus A5, A7, A9, A10, B2, and B5 strains. Enterovirus 71 (EV-71) has caused outbreaks of HFMD with associated neurologic involvement in the western Pacific region.

The lower lip has an ulcer with an erythematous haThe lower lip has an ulcer with an erythematous halo.

See Clues in the Oral Cavity: Are You Missing the Diagnosis?, a Critical Images slideshow, to help identify the causes of abnormalities of the oral cavity.

Also, see the 15 Rashes You Need to Know: Common Dermatologic Diagnoses slideshow to help identify and treat various rashes and the 15 Back-to-School Illnesses You Should Know slideshow to help identify conditions that may occur in young patients after they return to the classroom.

Signs and symptoms

The history in patients with HFMD is as follows:

  • Sore mouth or throat

  • Malaise

  • Rarely, vomiting occurs in HFMD cases caused by EV-71

Physical findings include the following:

  • Initially, macular lesions appear on the buccal mucosa, tongue, and/or hard palate

  • These mucosal lesions rapidly progress to vesicles that erode and become surrounded by an erythematous halo

  • Lesions may also be found on the hands, feet, buttocks, and genitalia

  • A fever of 38-39°C may be present for 24-48 hours

Atypical clinical features include concomitant aseptic meningitis in HFMD caused by coxsackievirus strains (rare). [1HFMD caused by EV-71 has a higher incidence of neurologic involvement, including the following [2:

  • A poliolike syndrome

  • Aseptic meningitis

  • Encephalitis

  • Encephalomyelitis

  • Acute cerebellar ataxia

  • Acute transverse myelitis

  • Guillain-Barré syndrome

  • Opsomyoclonus syndrome

  • Benign intracranial hypertension

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of HFMD is typically based on clinical grounds. Laboratory studies are usually unnecessary, but the following may be done:

  • The virus can be isolated and identified via culture and immunoassay from cutaneous lesions, mucosal lesions, or stool samples; oral specimens have the highest isolation rate

  • In patients with vesicles, vesicle swabs are also a good source for viral collection

  • In patients without vesicles, rectal swabs can be collected

  • For viral isolation, 2 swab collections are recommended: From the throat and from either vesicles or the rectum

  • Serologic testing (eg, acute and convalescent antibody levels) may be obtained

  • Differentiating coxsackievirus-associated HFMD from EV-71–associated HFMD may have prognostic significance

  • PCR and microarray technology are among the various ways of identifying the causative virus [3]

See Workup for more detail.

Management

There is no antiviral agent specific for the etiologic agents of HFMD. Instead, the treatment is supportive, as follows:

  • Ensure adequate fluid intake to prevent dehydration; cold liquids are generally preferable

  • Spicy or acidic substances may cause discomfort

  • Intravenous hydration may be necessary if the patient has moderate-to-severe dehydration or if discomfort precludes oral intake

  • Fever may be treated with antipyretics

  • Pain may be treated with standard doses of acetaminophen or ibuprofen

  • Direct analgesia may also be applied to the oral cavity via mouthwashes or sprays

  • IVIG and milrinone have shown some efficacy in a few reports [456]

See Treatment and Medication for more detail.

Background

Hand-foot-and-mouth disease (HFMD) is an acute viral illness that presents as a vesicular eruption in the mouth. HFMD can also involve the hands, feet, buttocks, and/or genitalia. Coxsackievirus A type 16 (CV A16) is the etiologic agent involved in most cases of HFMD, but the illness is also associated with coxsackievirus A5, A7, A9, A10, B2, and B5 strains. Enterovirus 71 (EV-71) has also caused outbreaks of HFMD with associated neurologic involvement in the western Pacific region.

Coxsackievirus is a subgroup of the enteroviruses and is a member of the family Picornaviridae. This family consists of small, nonenveloped, single-stranded RNA viruses.

Pathophysiology

Infection generally occurs via the fecal-oral route or via contact with skin lesions and oral secretions. Viremia develops, followed by invasion of the skin and mucous membranes. Widespread apoptosis likely results in the characteristic lesion formation.

Frequency

United States

Epidemics of HFMD generally occur in the summer to early fall months, although cases can occur sporadically all year.

International

HFMD epidemics associated with EV-71 have been more frequent in Southeast Asia in recent years, including Taiwan (1998) and Singapore (2000). Risk factors in these epidemics include attendance at child care centers, contact with HFMD, large family number, and rural residence. [7]

Mortality/Morbidity

HFMD caused by coxsackievirus is generally a mild self-limited illness that resolves in 7-10 days; rarely, HFMD may recur or persist. Serious complications are also rare.

Severe oral ulcerations can create painful stomatitis. This may interfere with oral intake and cause dehydration, the most common complication of HFMD. Rarely, aseptic meningitis accompanies coxsackievirus-induced HFMD.

HFMD caused by EV-71 has a higher incidence of neurologic involvement, including a poliolike syndrome, aseptic meningitis, encephalitis, encephalomyelitis, acute cerebellar ataxia, acute transverse myelitis, Guillain-Barré syndrome, opsomyoclonus syndrome, and benign intracranial hypertension. These neurological complications have been attributed to either immunopathology or virus-induced damage to gray matter. [18]

Rarely, cardiopulmonary complications such as myocarditis, interstitial pneumonitis, and pulmonary edema may occur. Neurologic involvement with sequelae is less likely to occur in patients with HFMD caused by coxsackievirus strains than with HFMD caused by EV-71. Chang et al analyzed the Taiwan HFMD epidemic of 1998 and revealed that 68% of the EV-71 cases were uncomplicated. [9Thirty-two percent of the cases had complications; 7.3% involved aseptic meningitis, 10% involved encephalitis, 2.3% involved poliolike syndrome, 4.5% involved encephalomyelitis, and 6.8% involved fatal pulmonary edema (7.9% of patients died and 4% of patients had sequelae). In the coxsackievirus A16 group, 94% of the cases of were uncomplicated; only 6.3% cases were complicated by aseptic meningitis; no fatalities or sequelae were reported.

Chong et al observed vomiting, leukocytosis, and an absence of mouth ulcers as predictive risk factors for fatal cases of EV-71 HFMD during the Singapore epidemic in 2000. [2]

Sex

Most reports indicate that HFMD has no sexual predilection. Some epidemic data observe a slight male-to-female predominance ratio of 1.2-1.3:1.

Age

Children younger than 10 years are most commonly affected with HFMD, and subsequent outbreaks among family members and close contacts may develop. 

CLINICAL PRESENTATION


History

The incubation period of hand-foot-and-mouth disease (HFMD) lasts approximately 1 week; patients then report a sore mouth or throat. Malaise may develop. Rarely, vomiting occurs in HFMD cases caused by EV-71.

Physical

Initially, macular lesions appear on the buccal mucosa, tongue, and/or hard palate. These mucosal lesions rapidly progress to vesicles that erode and become surrounded by an erythematous halo, as shown in the image below. Skin lesions, which present as tender macules or vesicles on an erythematous base, develop in approximately 75% of patients with HFMD. A fever of 38-39°C may be present for 24-48 hours.

The lower lip has an ulcer with an erythematous haThe lower lip has an ulcer with an erythematous halo.

Atypical clinical features may be present. HFMD caused by coxsackievirus strains rarely presents with concomitant aseptic meningitis. [1HFMD caused by EV-71 has a higher incidence of neurologic involvement, including a poliolike syndrome, aseptic meningitis, encephalitis, encephalomyelitis, acute cerebellar ataxia, acute transverse myelitis, Guillain-Barré syndrome, opsomyoclonus syndrome, and benign intracranial hypertension. [2]

Causes

HFMD is most commonly caused by coxsackievirus A16, but it is also caused by coxsackieviruses A5, A7, A9 A10, B2, and B5 and EV-71. Two major genotypes of EV-71, EV-71 B and C, have been identified as the strains principally involved in the EV-71 HFMD epidemics in Australia, Malaysia, Singapore, Taiwan, and Japan since 1997. These genotypes are considered particularly neurovirulent, accounting for the severe neurologic complications seen in EV-71 HFMD epidemics. 

DIFFERENTIAL DIAGNOSIS


Diagnostic Considerations

Table 1. Differential Diagnoses of Hand-Foot-and-Mouth Disease (Open Table in a new window)

Illness

Etiologic Agent

Usual Severity of Clinical Illness

Appearance of Lesions

Locations of Lesions

Other Features

HFMD

Coxsackie-virus A16 (most common), A5, A7, A9, A10, B2, B5

Enterovirus 71

Mild

Papules →

Vesicles → ulcerations on an erythematous base

Usually 2-6 mm

Gingiva

Buccal mucosa

Tongue

Pharynx

Lesions may also be found on hands, feet, buttocks, and genitalia.

Low-grade fever

Herpangina

Coxsackie-virus A1-A10, A16, A22

Echovirus 3, 6, 9, 16, 17, 25, 30

Moderate; can be severe

Papules →

Vesicles → ulcerations on an erythematous base

Usually 2-4 mm

Posterior oral cavity

Tonsils, soft palate, uvula

Temperature generally high

Herpetic gingivostomatitis

Herpes simplex virus-1

Moderate to severe

Vesicles

ulcerations

Anterior oral cavity

Lips, gingiva, buccal mucosa

Temperature generally high

Lymphadenopathy

Aphthous stomatitis

Unknown

Mild to severe

Ulcerations; larger than in viral enanthems

Lips, tongue, buccal mucosa; generally not diffuse

Afebrile

May be recurrent

Stevens-Johnson syndrome

Immunologic

Moderate to severe

Coalescent vesicles, which then ulcerate

Lips, gingiva, buccal mucosa, tongue, pharynx

Targetlike cutaneous lesions

Diffuse mucous membrane involvement

Differential Diagnoses

TREATMENT AND MANAGEMENT

Medical Care

The treatment of hand-foot-and-mouth disease (HFMD) is supportive. In fact, there is no antiviral agent specific for the etiologic agents. Ensure adequate fluid intake to prevent dehydration. Cold liquids are generally preferable. Spicy or acidic substances may cause discomfort. Intravenous hydration may be necessary if the patient has moderate-to-severe dehydration or if discomfort precludes oral intake. Fever may be treated with antipyretics. Pain may be treated with standard doses of acetaminophen or ibuprofen. Direct analgesia may also be applied to the oral cavity via mouthwashes or sprays. Intravenous immunoglobulin (IVIG) and milrinone have shown some efficacy in a few reports. [456]

There is a relative dearth of treatment options for enterovirus-associated HFMD cases. Recent research has yielded several promising novel and existing therapeutics targeting specific viral mechanisms of action. These include molecular decoys, receptor antagonists, uncoating and translation inhibitors, polyprotein processing inhibitors, and replication inhibitors. Pleconaril is an uncoating inhibitor that shows promise in enterovirus 71–associated infections.

Amantadine and quinacrine, both translation inhibitors, and ribavirin, a replication inhibitor, are also being investigated as treatment options. 

MEDICATION


Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antipyretics/analgesics

Class Summary

These agents are used to control fever and pain.

Acetaminophen (Tylenol, Aspirin Free Anacin, Feverall)

Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating.

Ibuprofen (Motrin, Ibuprin)

One of the few NSAIDs indicated for reduction of fever.

Topical anesthetics

Class Summary

These agents can be applied to ulcerations to control pain.

Lidocaine anesthetic (Dermaflex)

Decreases permeability to sodium ions in neuronal membranes. This results in the inhibition of depolarization, blocking the transmission of nerve impulses.

Antihistamines

Class Summary

These agents act by competitive inhibition of histamine at the H1 receptor.

Diphenhydramine hydrochloride (Benadryl, Benylin)

For symptomatic relief of symptoms caused by release of histamine in allergic reactions.

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