Can you explain hand‑foot‑and‑mouth disease, including its etiology, clinical presentation, diagnosis, management, and prevention?

Hand, Foot, and Mouth Disease: Clinical Overview

Etiology

Hand, foot, and mouth disease (HFMD) is a viral infection caused by enteroviruses of the Picornaviridae family, most commonly coxsackievirus A16 (CV-A16) and enterovirus A71 (EV-A71), though coxsackievirus A6 (CV-A6) and A10 are increasingly recognized as causative agents. 1, 2

• The disease primarily affects children under 5 years of age, though adults can be affected 3, 4
• EV-A71 infections are associated with more severe disease and higher complication rates compared to CV-A16 3, 5
• Recent epidemiological shifts show CV-A6 and CV-A10 causing more infections, with extensive recombination events among enterovirus strains 2
• In India specifically, CV-A16 remains the major circulating enterovirus type with B1c subgenotype predominance 1

Clinical Presentation

The disease manifests as a febrile illness followed by characteristic oral and cutaneous lesions, typically resolving in 7-10 days without sequelae. 3

Classic Features:

• Mild-to-moderate fever of short duration 1
• Painful oral enanthem presenting as vesicles that progress to multiple small superficial ulcers 3
• Asymptomatic exanthem on palms, soles, hands, feet, knees, elbows, and buttocks appearing as papulovesicular lesions 1, 3
• CV-A6 has been specifically associated with onychomadesis (nail shedding) 6

Severe Complications (Particularly with EV-A71):

Early recognition of severe cases is paramount, as progression can be rapid and life-threatening. 5

• Brainstem encephalitis and rhomboencephalitis 6, 5
• Meningitis and meningoencephalitis 6
• Acute flaccid myelitis/paralysis 6
• Myocarditis 6
• Neurogenic pulmonary edema secondary to brainstem damage 3
• Circulatory failure secondary to myocardial impairment 3

Warning Signs of Deterioration:

Clinicians should be particularly vigilant with EV-A71 cases in children under 3 years with disease duration less than 3 days. 5

The following indicators signal possible progression to critical disease 5:

1. Persistent hyperthermia
2. Nervous system involvement
3. Worsening respiratory rate and rhythm
4. Circulatory dysfunction
5. Elevated peripheral WBC count
6. Elevated blood glucose
7. Elevated blood lactic acid

Diagnosis

Reverse transcriptase PCR (RT-PCR) targeting the 5' non-coding region should be used for diagnosis due to superior sensitivity, specificity, and rapid turnaround time. 6

Sample Collection Strategy:

The choice of specimen depends on clinical presentation 6:

• HFMD/rash cases: Vesicle fluid (highest viral loads), respiratory samples, and/or stool 6
• Meningitis/encephalitis: CSF, stool AND respiratory sample, possibly blood 6
• Acute flaccid paralysis/myelitis: Respiratory, CSF, stool AND blood samples (respiratory specimens are essential as EV-D68 and EV-A71 may only be detectable in respiratory tract) 6
• Myocarditis: Stool and respiratory sample, blood and/or heart biopsy 6
• Conjunctivitis: Eye swab 6

Important Diagnostic Considerations:

• CSF may be acellular, especially in children under 3 months, despite active infection 6
• Viral loads are typically higher in stool, blood, and respiratory samples than CSF 6
• Virus can be detected in throat and stool for weeks to months, requiring cautious interpretation 6
• Sequencing of VP1 capsid protein gene is recommended for enterovirus typing; typing cannot be based on 5'NCR sequences due to frequent recombination 6

Management

Most mild cases require only symptomatic and supportive care with domiciliary management, as the disease is self-limiting. 7, 3

Mild Cases:

• Outpatient management with isolation to prevent cross-infection 5
• Symptomatic treatment for fever and pain 3
• Active communication and close monitoring are essential 7
• Counseling parents is an integral component of management 7

Severe/Complicated Cases:

Intravenous immunoglobulin (IVIG) should be considered for severe or complicated HFMD and has been recommended by several national and international guideline committees. 3

• Intensive treatment modalities for stage 2-3 disease to prevent progression to stage 4 5
• IVIG administration for severe cases 3
• Currently, no specific antiviral agents are approved for treatment 3
• Potential investigational agents include ribavirin, suramin, mulberroside C, aminothiazole analogs, and sertraline 3

Common Pitfall:

Do not delay recognition of severe disease—the key to successful management lies in timely and accurate recognition of stages 2 and 3 to prevent progression to critical stage 4 5

Prevention

Vaccination of susceptible individuals in high-risk areas and good personal hygiene are the primary preventative measures. 3

• EV-A71 vaccines have been approved and are currently used in mainland China 3, 2
• Disease spreads by fecal-oral, oral-oral, and respiratory droplet contact 7
• Isolation of affected individuals decreases outbreak risk 3
• No vaccines are currently available outside China for widespread use 2