How many different strains of hand, foot, and mouth disease (HFMD) are there?

How Many Different Strains of Hand, Foot, and Mouth Disease Exist

Hand, foot, and mouth disease (HFMD) is caused by multiple enterovirus strains, with the most common causative agents being enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), coxsackievirus A6 (CV-A6), and coxsackievirus A10 (CV-A10). 1

Main Causative Agents

The primary strains responsible for HFMD include:

1. Enterovirus A71 (EV-A71) - Associated with more severe neurological complications including:

   • Brain stem encephalitis
   • Meningoencephalitis
   • Acute flaccid paralysis
   • Pulmonary edema 2

2. Coxsackievirus A16 (CV-A16) - Traditionally one of the most common causes of typical HFMD 3, 2

3. Coxsackievirus A6 (CV-A6) - Emerged as a significant cause of HFMD since 2011, often causing atypical presentations 2

   • Associated with more severe symptoms than "classical" HFMD
   • Can affect adults as well as children
   • Linked to onychomadesis (nail shedding) occurring up to two months after initial symptoms 4

4. Coxsackievirus A10 (CV-A10) - Increasingly identified in recent outbreaks 1

Changing Epidemiology

The molecular epidemiology of HFMD-causing pathogens has been shifting:

• While EV-A71 and CV-A16 were traditionally the main causative agents, CV-A6 and CV-A10 have been causing more infections in recent years 1
• Multiple sub-genogroups of EV-A71 have been identified in various outbreaks:
  • Sub-genogroups C1, C2, B3, and B4 co-circulated in Malaysia in 1997
  • Sub-genogroups C1 and B4 caused outbreaks in 2000
  • Sub-genogroup B5 (with some C1) caused outbreaks in 2003
  • Distinct clusters of sub-genogroup B5 were responsible for outbreaks in 2005-2006 5

Genetic Diversity and Evolution

• Extensive recombination events have been identified among enterovirus strains, contributing to faster evolution and extinction of dominant enterovirus serotypes 1
• Sequencing of the VP1 capsid protein gene is recommended for enterovirus typing, as typing cannot be based on the 5′NCR sequences due to frequent recombination events 3
• Epidemiological patterns show recurrence of HFMD due to EV-A71 every 2-4 years, with more than one sub-genogroup co-circulating in each outbreak 5

Clinical Implications

The diversity of HFMD strains has important clinical implications:

• Different strains can cause varying clinical presentations, from mild typical HFMD to severe neurological complications
• Atypical presentations (particularly with CV-A6) can include:
  • Gianotti-Crosti-like eruptions
  • Eczema coxsackium
  • Petechial/purpuric eruptions
  • Vesiculobullous exanthema 6
• These atypical presentations may mimic other serious skin conditions such as eczema herpeticum, varicella, disseminated zoster, and erythema multiforme major 6

Diagnostic Considerations

For accurate identification of the specific strain:

• Reverse transcriptase PCR (RT-PCR) targeting the 5′non-coding regions should be used for initial diagnosis due to sensitivity, specificity, and short turnaround time 3
• Sequencing of the VP1 capsid protein gene is recommended for enterovirus typing 3
• Appropriate samples for testing include:
  • Vesicle fluid (high viral loads)
  • Respiratory samples
  • Stool samples 3

The diversity of HFMD strains underscores the importance of accurate diagnosis and surveillance to monitor emerging strains and their potential for causing severe disease.