Hand-foot-mouth disease (HFMD) is an acute febrile exanthematous disease caused by enteroviruses. Clinically, it is characterized by the appearance of maculopapular and vesicular rashes on the hands, feet, and oral mucosa. A small number of patients experience rapid disease progression, which may lead to severe complications such as encephalitis, neurogenic pulmonary edema, and circulatory failure.
Etiology
Enteroviruses (EV) belong to the genus Enterovirus in the family Picornaviridae. These viruses are non-enveloped and have an outer capsid. Their genome consists of single-stranded positive-sense RNA. The main viral proteins include four structural capsid proteins (VP1, VP2, VP3, and VP4) and seven non-structural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D). The primary causative agents are enterovirus 71 (EV71) and Coxsackievirus A16 (CV-A16), although in recent years, infections caused by CV-A6 and CV-A10 have also shown an increasing trend. Enteroviruses are highly diverse, and there is generally no cross-immunity between serotypes. These viruses share similar physicochemical and biological properties, being small icosahedral particles with a diameter of 24–30 nm. They are highly resistant to environmental factors, including low temperatures and acidic conditions, but are extremely sensitive to oxidizing agents such as free chlorine and potassium permanganate, as well as to heat, desiccation, and ultraviolet light. They can survive up to one year at 4°C and can be preserved for extended periods at temperatures below -20°C.
Epidemiology
Both patients and asymptomatic carriers act as sources of infection. Transmission primarily occurs through the digestive tract but can also result from contact with respiratory secretions, vesicular fluid, or contaminated objects from infected individuals. Children are universally susceptible, with the highest incidence observed in infants and young children under the age of three. HFMD is highly contagious, and outbreaks often occur in daycare centers and family clusters during epidemic periods. The disease exhibits a cyclical pattern, with outbreaks typically occurring every 2–3 years.
Pathogenesis
The pathogenesis of HFMD, particularly EV71 infections, remains incompletely understood. Enteroviruses invade the host through the digestive or respiratory tract, replicate locally in mucosal or lymphoid tissues, and subsequently enter the bloodstream, leading to viremia. The virus is then disseminated via the bloodstream to the meninges, brain, spinal cord, heart, skin, mucosa, and other organs, where it continues to replicate. In most cases, host defense mechanisms limit the infection, leading to asymptomatic cases or mild clinical manifestations. In rare cases, extensive viral replication occurs in target organs, resulting in severe infections. Specific antibodies (IgM, IgG, and IgA) and mucosal IgA in the intestines are produced approximately one week after infection, reaching peak levels within 3–4 weeks. These provide partial protection against viruses of the same serotype but do not prevent infection with different enterovirus serotypes.
Pathology
Central nervous system lesions primarily involve the brainstem but may also extend to the hypothalamus, thalamus, dentate nucleus, and cerebral cortex. Key pathological changes include neuronal degeneration, necrosis, and softening of brain tissue, perivascular cuffing, neuronophagia, infiltration of mononuclear macrophages into brain parenchyma, and diffuse or nodular proliferation of microglial cells. Pulmonary lesions include dilatation and congestion of alveolar capillary walls, extensive mononuclear cell infiltration, formation of hyaline membranes, hemorrhagic infarction, and accumulation of edema within the alveolar spaces. Cardiac involvement is characterized by focal inflammatory cell infiltration of the endocardium, myocardium, and interstitial tissues, along with vascular congestion in the cardiac stroma. Ventricular biopsy may reveal myocardial cell necrosis, myofiber degeneration, and apoptosis of cardiomyocytes.
Clinical Manifestations
The incubation period ranges from 2 to 14 days, commonly lasting 3 to 5 days. Clinical manifestations are complex and variable. Cases are classified into mild cases and severe cases based on the severity of the disease.
Mild Cases
The onset is acute, with or without fever. Nonspecific symptoms such as cough, nasal discharge, and loss of appetite are often present. Sporadic rashes and vesicles can be observed on the hands, feet, mouth, and buttocks, occasionally involving the trunk. Vesicles in the oral cavity are mostly located on the tongue, buccal mucosa, and hard palate, often accompanied by ulceration. The rashes usually resolve without leaving scars or pigmentation. There are no signs of complications, and recovery usually takes place within one week with a good prognosis.
Severe Cases
In rare cases, the condition progresses rapidly in addition to the clinical manifestations of hand-foot-mouth disease. These cases are defined as severe when accompanied by complications involving any of the following systems:
Nervous System
Symptoms include persistent high fever, headache, vomiting, lethargy, somnolence, irritability, easy startling, delirium, and even coma. Other signs include limb tremors, myoclonus, nystagmus, ataxia, impaired ocular motility, muscle weakness, acute flaccid paralysis, and seizures. Neck stiffness is more obvious in children over 1–2 years old, with reduced or absent deep tendon reflexes and positive meningeal irritation signs.
Respiratory System
Symptoms may include shallow, rapid breathing, respiratory distress, altered breathing rhythm, cyanosis of the lips, worsening cough, and production of white, pink, or blood-tinged frothy sputum. Wet rales may be heard in the lungs.
Circulatory System
Symptoms may include an increased or decreased heart rate, pale gray complexion, mottled skin, cold extremities, excessive sweating, and peripheral cyanosis of the fingers and toes. Persistent hypotension and prolonged capillary refill time may also occur.
Laboratory Examinations
Complete Blood Count (CBC)
The white blood cell (WBC) count is often normal or decreased. In severe cases, a marked increase in WBC count can be observed.
Biochemical Testing
Some patients may show mildly elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase-MB (CK-MB). Severe cases may present elevated levels of cardiac troponin I (cTnI) and blood glucose.
Arterial Blood Gas Analysis
Respiratory involvement may result in reduced arterial oxygen partial pressure, decreased oxygen saturation, elevated carbon dioxide partial pressure, and signs of acidosis.
Cerebrospinal Fluid (CSF) Analysis
Nervous system involvement may present with clear CSF appearance, elevated pressure, increased WBC count, normal or slightly elevated protein levels, and normal glucose and chloride levels.
Etiological Testing
Positive results for enterovirus-specific nucleic acid or isolation of enterovirus from nasopharyngeal swabs, airway secretions, vesicular fluid, or stool samples confirm the diagnosis.
Serological Testing
Positive enterovirus-specific IgM antibody in the acute phase or a fourfold or greater increase in specific IgG antibody titers in paired serum samples is diagnostic.
Imaging Studies
Chest X-rays may reveal bilateral lung markings, reticular or patchy shadows, and in some cases, unilateral predominance. Magnetic resonance imaging (MRI) in cases of nervous system involvement may show abnormal changes predominantly affecting the brainstem and spinal gray matter.
Diagnosis and Differential Diagnosis
Clinical diagnosis can often be made based on epidemiological data and the presence of characteristic rashes on the hands, feet, mouth, and buttocks. For severe cases with atypical rashes, clinical diagnosis may be challenging and require additional etiological or serological testing. Close monitoring and timely medical intervention are warranted for patients, particularly those under the age of three, who exhibit the following signs indicating potential progression to critical illness:
- Persistent high fever that does not resolve.
- Lethargy, vomiting, easy startling, limb tremors, or weakness.
- Increased respiratory rate and heart rate.
- Excessive sweating, cold extremities, and poor peripheral circulation.
- Hypertension.
- Marked elevation of WBC count and platelet count in peripheral blood.
- High blood glucose levels.
Differentiation from other conditions that cause fever and rash in children is necessary, including diseases such as viral encephalitis or meningitis, pneumonia, or fulminant myocarditis caused by other viruses.
Treatment
Mild Cases
There are currently no specific antiviral drugs or targeted treatments. Symptomatic care is the main approach. Isolation is recommended to prevent cross-infection. Adequate rest, a light diet, and proper oral and skin care are essential.
Severe Cases
Treatment for Nervous System Involvement
Intracranial pressure should be managed by controlling fluid intake and administering mannitol. A dose of 0.5–1.0 g/kg can be given by rapid intravenous injection over 20–30 minutes every 4–8 hours. The interval and dosage can be adjusted based on the condition. In some cases, furosemide may also be used.
Glucocorticoid therapy can be considered as needed. Suggested dosages include methylprednisolone (1–2 mg/kg/day), hydrocortisone (3–5 mg/kg/day), or dexamethasone (0.2–0.5 mg/kg/day). Dosage should be reduced or discontinued promptly once the condition stabilizes.
Intravenous immunoglobulin (IVIG) can be administered when indicated, with a total dose of 2 g/kg given over 2–5 days.
Symptomatic treatments, including antipyretics, sedatives, and anticonvulsants, may also be used, along with close monitoring of the patient’s condition.
Management of Respiratory or Circulatory Failure
This involves:
- Maintaining airway patency and providing oxygen supplementation.
- Monitoring respiratory rate, heart rate, blood pressure, and oxygen saturation.
- Treating respiratory dysfunction as per relevant guidelines.
- Preserving the function of vital organs and maintaining homeostasis.
Recovery Phase Treatment
This includes:
- Measures to promote recovery of organ function.
- Rehabilitation therapy.
Prevention and Prognosis
Mild cases can be managed with home isolation, while severe cases require hospitalization at designated facilities for isolation and treatment. Enhanced epidemic surveillance and prompt isolation of suspected cases in daycare centers and other group settings are necessary. Vaccination with the EV-71 inactivated vaccine effectively reduces the risk of EV-71 infection in children and is recommended for those aged 6 months to 5 years. The standard immunization schedule involves two doses given one month apart, with completion recommended before 12 months of age. Mild cases typically resolve within about one week with a favorable prognosis. Severe cases, however, carry a high risk of critical complications and elevated mortality rates.