Is hand, foot, and mouth disease (HFMD) part of the spectrum of illnesses caused by enteroviruses (EVs)?

Hand, Foot, and Mouth Disease is Definitively Caused by Enteroviruses

Yes, hand, foot, and mouth disease (HFMD) is definitively part of the spectrum of illnesses caused by enteroviruses (EVs). 1 This relationship is well-established in medical literature and recognized in clinical guidelines.

Enterovirus Types Associated with HFMD

HFMD is caused by several specific enterovirus types:

• Primary causative agents:

  • Enterovirus A71 (EV-A71) - associated with severe outbreaks and neurological complications 1, 2
  • Coxsackievirus A16 (CA16) - traditionally common cause 3
  • Coxsackievirus A6 (CA6) - increasingly common in recent years 3, 4
  • Coxsackievirus A10 (CA10) - less common cause 3, 5
  • Coxsackievirus A4 (CA4) - less common cause 5

• Epidemiological shifts:

  • In many regions, CA6 has been gradually replacing EV-A71 and CA16 as the predominant cause of mild HFMD 3
  • At least 20 different enterovirus types have been associated with HFMD 6

Clinical Presentation and Severity

HFMD presents with characteristic symptoms:

• Typical manifestations:

  • Fever and sore throat as initial symptoms 4
  • Maculopapular or vesicular eruptions on palms, soles, and oral cavity 4
  • Incubation period of 3-10 days 4

• Serotype-specific presentations:

  • EV-A71: More likely to cause severe disease with neurological complications 1, 3
  • CA6: More frequent mouth vesicles, can affect adults more often than other types 3, 4
  • CA10: Less likely to develop vesicles on extremities but more likely to cause fever and pharyngalgia 3

Severe Complications

While HFMD is typically self-limiting, severe complications can occur:

• Neurological complications:

  • Primarily associated with EV-A71 infections 1, 2, 3
  • Include aseptic meningitis, encephalitis, and rhombencephalitis 1, 2
  • Myoclonic jerks and vomiting are common severe symptoms 3

• Other severe manifestations:

  • Cardiopulmonary failure (rare but potentially fatal) 2
  • In China, case severity rate estimated at 1%, with case fatality rate at 0.03% 2
  • EV-A71 involved in >90% of fatal cases 2

Diagnostic Considerations

For suspected HFMD with neurological involvement:

• Sample collection:

  • Multiple samples should be collected: vesicle fluid, throat swabs, stool samples 1, 2
  • Stool samples have the highest diagnostic yield (89%), followed by rectal swabs (77%) and throat swabs (74%) 5
  • Combined testing of stool and throat swabs increases detection rates to 93% 5

• Testing methods:

  • RT-PCR targeting the 5' non-coding region for initial detection 1
  • VP1 capsid protein gene sequencing for enterovirus typing 1
  • Note that EV-A71 is rarely recovered from CSF even in neurological disease 2

Prevention and Management

• Treatment:

  • Mostly symptomatic for uncomplicated cases 4
  • Severe cases may require mechanical ventilation and antiviral agents like ribavirin 4

• Vaccines:

  • Inactivated EV-A71 vaccines available in China since 2016 6
  • These vaccines do not cross-protect against other HFMD-causing enteroviruses 6
  • Multivalent vaccines targeting multiple enterovirus types are in development 6

Clinical Pearls and Pitfalls

• Atypical presentations:

  • HFMD can present with atypical skin manifestations that may be confused with other conditions 2
  • Delayed cutaneous manifestations like onychomadesis (nail shedding) may occur weeks after initial infection, particularly with CA6 2, 4

• Age considerations:

  • CA6, CA10, and CA4 infections tend to affect younger children (median age 12 months) compared to EV-A71 and CA16 (median age 24 months) 5
  • Adults can also develop HFMD, particularly with CA6 infections 4

• Surveillance importance:

  • Monitoring HFMD is crucial for early detection of EV-A71 outbreaks 1, 2
  • Continued surveillance is essential following EV-A71 vaccine implementation to monitor for serotype replacement 5, 6