Hand-Foot-and-Mouth Disease (HFMD)

Hand-foot-and-mouth disease (HFMD) is an acute viral illness first evident 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. Coxsackievirus A6 may have become the commonest enterovirus in seasonal outbreaks of hand-foot-and-mouth disease in children in parts of Europe.[2]  

Enterovirus 71 (EV-71) has also caused outbreaks of HFMD with associated neurologic involvement in the western Pacific region and Southeast Asia.

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.

United States

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

International

Hand, foot and mouth disease (HFMD) has become a societal burden in parts of Asia with pandemic potential.[9]  HFMD epidemics associated with EV-71 have been more frequent in Southeast Asia in recent years, including the Republic of China (1998) and Singapore (2000). Risk factors in these epidemics include attendance at child care centers, contact with HFMD, large family number, and rural residence.[10] Seasonal trends and climate factors may be evident and were delineated in Guangzhou (Canton) China.[1]  The incidence of HFMD is increasing despite current preventive efforts in Singapore.[11]

Hand, foot and mouth disease 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.

Hand, foot and mouth disease 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.[3, 12]

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.[13] 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

HandMost 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; subsequent outbreaks among family members and close contacts may develop.[14]

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.

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 halo.

Atypical clinical features may be present. HFMD caused by coxsackievirus strains rarely presents with concomitant aseptic meningitis.[3] 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]

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, Republic of China, and Japan since 1997. These genotypes are considered particularly neurovirulent, accounting for the severe neurologic complications seen in EV-71 HFMD epidemics.[15]

The diagnosis of hand-foot-and-mouth disease (HFMD) is typically based on clinical grounds. Laboratory studies are usually unnecessary. However, when it mimics Stevens-Johnson Syndrome[17]  or erythema multiforme,[18]  a skin biopsy specimen would be desirable.

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.[5]

The treatment of hand-foot-and-mouth disease (HFMD) is supportive.[19] 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.[6, 7, 8]

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.[20]

A vaccine would be desirable, especially against the Enterovirus A71 (EV-A71).[21]  EV71 vaccine in China was found effective in prevention, with CA16 and EV71 proportions found inversely related to the vaccination rate in Canton (Guangzhou), China.[1]  It may have a protective effect on the occurrence of encephalitis, which may still may develop.[22]  Bivalent enterovirus 71 (EV71) and coxsackievirus A16 (CA16) vaccines may be advantageous.[23] There is no vaccine available in American or the European Union at present.

A suitable mitigation strategy to minimize enterovirus transmission among children with HFMD to control severe EV epidemics may be case isolation and class suspension if more than two having an onset of HFMD in one classroom within one week.[24]

Care with sample collection is desirable, as puncture with a contaminated lancet may produce severe HFMD.[25]

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

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.

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.

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.

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.

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

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.

The prognosis of HFMD is excellent. The vast majority of patients with this infection are expected to recover fully.  Age greater than 3 years, enterovirus 71 autonomic nervous system dysregulation, pulmonary edema/hemorrhage, C-reactive protein greater than 40 mg/L, and cardiac troponin more than 0.04 ng/ml were risk factors for fatality in a study from Guangzhou (Canton), China.[19]