eMedicine Specialties > Infectious Diseases > Skin and Soft-Tissue Infections

Hand-Foot-and-Mouth Disease

Stephen J Nervi, MD, Staff Physician, Department of Dermatology, University of Medicine and Dentistry of New Jersey, New Jersey School of Medicine
Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Rajendra Kapila, MD, MBBS, Professor of Medicine, Department of Medicine, UMDNJ, New Jersey Medical School; Diane H Johnson, MD, Assistant Director, Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, Winthrop-University Hospital, State University of New York at Stony Brook School of Medicine

Updated: Oct 22, 2009

Introduction

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.

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.^1,2
• 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.³ 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 2000.⁴

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.⁵

Clinical

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.
• 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.
• Atypical clinical features
  • HFMD caused by coxsackievirus strains rarely presents with concomitant aseptic meningitis.¹
  • 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.⁴

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.⁶

Differential Diagnoses

Other Problems to Be Considered

Differential Diagnoses of Hand-Foot-and-Mouth Disease

Workup

Laboratory Studies

• The 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.⁷

Treatment

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.^8,9,10

Medication

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

Antipyretics/analgesics

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.

Dosing

Adult

325-650 mg PO q4-6h or 1000 mg tid/qid; not to exceed 4 g/d

Pediatric

<12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d
>12 years: 325-650 mg PO q4h; not to exceed 5 doses in 24 h

Interactions

Rifampin can reduce analgesic effects of acetaminophen; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity

Contraindications

Documented hypersensitivity; known G-6-PD deficiency

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hepatotoxicity possible in persons with chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate a serious illness; acetaminophen is contained in many OTC products, and combined use with these products may result in cumulative acetaminophen doses exceeding recommended maximum dose

Ibuprofen (Motrin, Ibuprin)

One of the few NSAIDs indicated for reduction of fever.

Dosing

Adult

200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d

Pediatric

<6 months: Not established
6 months to 12 years: 4-10 mg/kg/dose PO tid/qid
>12 years: Administer as in adults

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

Contraindications

Documented hypersensitivity; peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency, or high risk of bleeding

Precautions

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

Topical anesthetics

These agents can be applied to ulcerations to control pain.

Lidocaine (Dermaflex)

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

Dosing

Adult

Apply to the affected area prn

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; avoid use in Adams-Stokes syndrome and Wolff-Parkinson-White syndrome

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

For external or mucous membrane use only; do not use in eyes

Antihistamines

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.

Dosing

Adult

25-50 mg PO q6-8h prn; not to exceed 400 mg/d
10-50 mg IV/IM q6-8hprn; not to exceed 400 mg/d

Pediatric

12.5-25 mg PO tid/qid, or 5 mg/kg/d, or 150 mg/m²/d divided tid/qid; not to exceed 300 mg/d
5 mg/kg/d IV/IM or 150 mg/m²/d, divided qid; not to exceed 300 mg/d

Interactions

Potentiates effect of CNS depressants; because of alcohol content, do not administer syrup dosage form to patients taking medications that can cause disulfiramlike reactions

Contraindications

Documented hypersensitivity; MAOIs

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; xerostomia may occur

Follow-up

Further Inpatient Care

• Patients with CNS manifestations of hand-foot-and-mouth disease (HFMD; eg, encephalitis, aseptic meningitis) may require hospitalization.

Further Outpatient Care

• Closely observe infants with HFMD 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 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

• The prognosis of HFMD is excellent. The vast majority of patients with this infection are expected to recover fully.

Miscellaneous

Medicolegal Pitfalls

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

References

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Keywords

hand-foot-and-mouth disease, HFMD, coxsackievirus, exanthematous eruptions, enterovirus 71, EV-71, Picornaviridae, aseptic meningitis, encephalitis, encephalomyelitis, mucosal lesions, mucocutaneous lesions, coxsackievirus A type 16, CV A16

Contributor Information and Disclosures

Author

Stephen J Nervi, MD, Staff Physician, Department of Dermatology, University of Medicine and Dentistry of New Jersey, New Jersey School of Medicine
Stephen J Nervi, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Rajendra Kapila, MD, MBBS, Professor of Medicine, Department of Medicine, UMDNJ, New Jersey Medical School
Rajendra Kapila, MD, MBBS is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America, and Infectious Diseases Society of New Jersey
Disclosure: Nothing to disclose.

Diane H Johnson, MD, Assistant Director, Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, Winthrop-University Hospital, State University of New York at Stony Brook School of Medicine
Diane H Johnson, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Women's Association, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Medical Editor

Gary L Gorby, MD, Program Director of Adult Infectious Diseases Fellowship, Associate Professor, Department of Internal Medicine, Division of Infectious Disease, St Joseph Medical Center, Creighton University School of Medicine
Gary L Gorby, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Thomas M Kerkering, MD, Chief of Infectious Diseases, Virginia Tech, Carilion School of Medicine, Roanoke, Virginia
Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

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