AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 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.

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.
• 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.¹ Thirty-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 no sex 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, and subsequent outbreaks among family members and close contacts may develop.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The incubation period lasts approximately 1 week; patients then report a sore mouth or throat.
• Malaise may develop.
• Rarely, vomiting occurs in infections 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.
• Skin lesions, which present as tender macules or vesicles on an erythematous base, develop in approximately 75% of patients with hand-foot-and-mouth disease (HFMD).
• A fever of 38-39°C may be present for 24-48 hours.
• Atypical clinical features  
• • HFMD caused by coxsackievirus strains rarely presents with concomitant aseptic meningitis.
  • 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.

Causes

• HFMD is most commonly caused by coxsackievirus A16, but it is also caused by coxsackieviruses A5, A7, A9 A10, B2, 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Differential Diagnoses of Hand-Foot-and-Mouth Disease

Illness	Etiologic Agent	Usual Severity of Clinical Illness	Appearance of Lesions	Locations of Lesions	Other Features
HFMD	Coxsackievirus 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	Coxsackievirus 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

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Diagnosis of hand-foot-and-mouth disease (HFMD) is typically based on clinical grounds. Laboratory studies are usually unnecessary.
• 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 the other from either vesicles or the rectum.
• Serologic testing (eg, acute and convalescent antibody levels) may be obtained.
• Differentiating coxsackie-associated from EV-71–associated HFMD may have prognostic significance. Polymerase chain reaction (PCR) and microarray technology are among the various ways of identifying the causative virus. Specific assays vary between hospitals.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The treatment of hand-foot-and-mouth disease (HFMD) is supportive. 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.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Antipyretics/analgesics

These agents are used to control fever and pain.

Drug Name	Ibuprofen (Motrin, Ibuprin)
Description	One of the few NSAIDs indicated for reduction of fever.
Adult Dose	200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d
Pediatric Dose	<6 months: Not established 6 months to 12 years: 4-10 mg/kg/dose PO tid/qid >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency, or high risk of bleeding
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Drug Category: Topical anesthetics

These agents can be applied to ulcerations to control pain.

Drug Category: Antihistamines

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients with CNS manifestations (eg, encephalitis, aseptic meningitis) may require hospitalization.

Further Outpatient Care

• Closely observe infants for development of dehydration.
• Clinical improvement is observed after approximately 3-5 days; cutaneous and mucosal lesions resolve in 7-10 days. The patient may continue to shed virus through the stool for weeks.

Complications

• Rarely, aseptic meningitis and other neurological complications accompany hand-foot-and-mouth disease (HFMD). More commonly, oral ulcerations can interfere with fluid intake and cause dehydration, the most common complication of HFMD.
• Rare case reports show spontaneous abortions associated with HFMD.

Prognosis

• Prognosis is excellent. The vast majority of patients are expected to recover fully.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to make the diagnosis
• Failure to maintain adequate hydration
• Failure to recognize rare but serious neurological complications

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Mar 17, 2008