Hand-Foot-and-Mouth Disease (HFMD)

Introduction

Hand-Foot-and-Mouth Disease (HFMD) is a common, highly contagious viral illness that predominantly affects infants and young children. It is characterized by a distinct clinical syndrome involving a vesicular exanthem on the hands and feet and an enanthem in the oral cavity. While typically a benign and self-limiting condition caused by Coxsackievirus A16, the emergence of Enterovirus 71 (EV71) and Coxsackievirus A6 (CVA6) has changed the clinical landscape, introducing risks of severe neurological complications and atypical cutaneous manifestations.

Etiology

HFMD is caused by viruses belonging to the genus Enterovirus within the family Picornaviridae. These are small, non-enveloped, single-stranded RNA viruses.

• Coxsackievirus A16 (CVA16): Historically the most common cause of classic HFMD. It typically results in a mild, self-limiting disease.
• Enterovirus 71 (EV71): A neurotropic serotype associated with large outbreaks in East and Southeast Asia. It is of significant public health concern because it can cause severe neurological and cardiopulmonary complications, including brainstem encephalitis and fatal pulmonary edema.
• Coxsackievirus A6 (CVA6): Recently emerged as a major cause of "atypical" HFMD. Infections with CVA6 are often more severe, affecting broader age groups (including adults) and presenting with more extensive skin involvement.
• Other Serotypes: Coxsackieviruses A5, A7, A9, A10, B2, and B5 can also cause HFMD.

Epidemiology

• Age: The disease primarily affects children younger than 5 to 10 years. Infants and toddlers are most susceptible. However, during outbreaks of CVA6, older children and adults are increasingly affected.
• Transmission:
  • Direct Contact: Contact with infectious virus in nose and throat secretions, saliva, fluid from blisters, or stool of infected persons.
  • Respiratory: Droplet spread through coughing or sneezing.
  • Fomites: Contact with contaminated objects and surfaces.
• Infectivity: Patients are most contagious during the first week of illness. However, the virus can be shed in the stool for weeks after symptoms resolve.
• Seasonality: In temperate climates, cases peak in late summer and early autumn. In tropical countries like India, the disease may occur year-round or show increased incidence during the rainy season.

Pathogenesis

1. Entry: The virus enters via the oral or respiratory route.
2. Replication: Initial replication occurs in the lymphoid tissues of the pharynx (tonsils) and the distal small intestine (Peyer's patches).
3. Viremia: The virus spreads to regional lymph nodes and then into the bloodstream (minor viremia).
4. Dissemination: The virus disseminates to reticuloendothelial tissues and target organs, including the skin, mucous membranes, and, in neurotropic strains like EV71, the central nervous system (CNS).
5. Immunity: Infection confers serotype-specific immunity, but cross-protection against other enteroviruses is limited; thus, recurrent episodes caused by different serotypes can occur.

Clinical Manifestations

The incubation period is typically 3 to 7 days.

1. Prodrome

The illness usually begins with a mild prodrome lasting 12 to 24 hours:

• Low-grade fever (though high fever can occur, especially with CVA6).
• Malaise, anorexia, and irritability.
• Sore throat or mouth pain.

2. Enanthem (Oral Lesions)

• Appearance: Small, red macules appear on the tongue, buccal mucosa, hard palate, gums, and pharynx. These rapidly progress to vesicles and then erode to form shallow, yellow-gray ulcers with an erythematous halo.
• Symptoms: The ulcers are painful, leading to drooling, difficulty swallowing (odynophagia), and refusal to eat or drink, which is a common cause of dehydration in young children.

3. Exanthem (Skin Lesions)

• Distribution: Lesions typically appear on the palms of the hands, soles of the feet, and buttocks. They may also appear on the knees, elbows, and genital area.
• Morphology:
  • Starts as erythematous macules or papules.
  • Progresses to distinct, gray, oval/elliptical vesicles (often described as "football-shaped") surrounded by a rim of erythema.
  • The vesicles on the palms and soles are firm and deep-seated.
  • Lesions on the buttocks usually present as a papular rash rather than frank vesicles.
  • The rash is usually non-pruritic (not itchy), though CVA6 infections can be itchy.
• Resolution: Skin lesions resolve in about 1 week (5–7 days) without scarring.

4. Atypical HFMD (Coxsackievirus A6)

Infection with CVA6 presents with a more severe and atypical phenotype:

• Wider Distribution: Rash extends to the trunk, face (perioral), and proximal extremities.
• Eczema Coxsackium: In children with atopic dermatitis, the virus can colonize eczematous areas, causing a severe, disseminated vesicular eruption resembling eczema herpeticum.
• Bullous Lesions: Large bullae may form.
• Desquamation: Delayed peeling of the skin on palms and soles may occur 1–3 weeks later.

Complications

While most cases are benign, complications can occur, particularly with specific serotypes.

1. Dehydration

The most common complication, resulting from refusal to feed due to painful oral ulcers.

2. Neurological Complications (Enterovirus 71)

EV71 is highly neurotropic and can cause severe CNS disease, typically 2–5 days after onset:

• Aseptic Meningitis: Headache, vomiting, stiff neck.
• Brainstem Encephalitis: The most critical form, presenting with myoclonus (jerks), tremor, ataxia, and cranial nerve palsies. Myoclonus is a key early warning sign.
• Acute Flaccid Paralysis: Polio-like limb weakness.

3. Cardiopulmonary Failure

Neurogenic pulmonary edema and hemorrhage can occur rapidly in severe EV71 brainstem encephalitis. This is characterized by tachycardia, respiratory distress, and pink frothy sputum, often leading to circulatory collapse (shock) and death.

4. Nail Changes (Onychomadesis)

Painless shedding of fingernails or toenails may occur 4 to 8 weeks after the acute infection. It is temporary, and nails regrow spontaneously. This is strongly associated with CVA6 infection.

Diagnosis

Diagnosis is primarily clinical based on the characteristic distribution of lesions.

1. Clinical Diagnosis

• Presence of oral ulcers combined with vesicular rash on hands and feet in a young child.
• Atypical cases: May be harder to diagnose and require a high index of suspicion, especially if the rash is generalized or bullous.

2. Laboratory Diagnosis

Laboratory confirmation is generally not required for mild cases but is crucial for severe cases or outbreaks.

• Virus Isolation/Culture: The gold standard but slow. Virus can be isolated from throat swabs, stool, or vesicle fluid.
• Molecular Testing (RT-PCR): The method of choice for rapid diagnosis. It is highly sensitive and can identify the specific serotype (e.g., differentiating EV71 from CVA16). Samples can be taken from throat, stool, vesicle fluid, or CSF (in neurological cases).
• Serology: Not useful for acute diagnosis due to the time lag in antibody production and high prevalence of background immunity.

Differential Diagnosis

• Herpangina: Also caused by enteroviruses. Characterized by high fever and ulcers on the posterior pharynx (anterior pillars, soft palate) without skin rash.
• Herpetic Gingivostomatitis: Caused by HSV. Presents with high fever, swollen bleeding gums (gingivitis), and perioral vesicles. Lesions are often more anterior in the mouth compared to the posterior distribution of herpangina.
• Varicella (Chickenpox): Rash is centripetal (concentrated on trunk/face/scalp), pruritic, and lesions are in different stages of healing (pleomorphism). HFMD rash is centrifugal (hands/feet) and lesions are uniform.
• Erythema Multiforme: Target lesions, often a history of drug intake or preceding HSV infection.
• Insect Bites: Papular urticaria, usually itchy and grouped.

Management

There is no specific antiviral therapy for HFMD. Management is supportive.

1. Supportive Care

• Hydration: Encouraging adequate fluid intake is the priority. Cold, non-acidic fluids (milk, ice cream, yogurt) are better tolerated.
• Analgesia: Paracetamol or Ibuprofen for fever and pain control. Avoid aspirin due to Reye syndrome risk.
• Topical agents: Oral anesthetic gels/sprays may help with painful swallowing (use with caution in young infants to avoid choking or toxicity).

2. Hospitalization Indications

• Severe dehydration requiring IV fluids.
• Neurological warning signs: Persistent vomiting, severe headache, myoclonus, lethargy, or limb weakness.
• Hemodynamic instability: Tachycardia, respiratory distress, poor perfusion (cold extremities).

3. Management of Severe EV71 Disease

• Intravenous Immunoglobulin (IVIG): Often used in severe cases with neurological involvement (encephalitis) to modulate the immune response, although evidence is observational.
• Milrinone: May be used in patients with signs of autonomic dysfunction and early cardiac failure to prevent pulmonary edema.

Prevention and Control

• Hygiene: Hand washing is the most effective preventive measure, especially after diaper changes.
• Isolation: Affected children should be kept out of school/daycare during the acute febrile phase and while drooling or having open blisters. Exclusion until all lesions are dry is standard in many settings, though viral shedding persists longer.
• Disinfection: Enteroviruses are non-enveloped and resistant to alcohol-based sanitizers. Surfaces should be cleaned with chlorine-containing disinfectants (bleach).
• Vaccination: Inactivated EV71 vaccines are approved and available in China but are not yet included in global immunization programs. There is no vaccine for CVA16 or CVA6.

Summary Table: Key Features of HFMD