Hand, Foot, and Mouth Disease Etiology
Yes, Hand, Foot, and Mouth Disease (HFMD) is caused by enteroviruses, most commonly coxsackievirus A16 (CV-A16), enterovirus 71 (EV-A71), and increasingly coxsackievirus A6 (CV-A6). 1, 2
Primary Causative Agents
HFMD is definitively an enteroviral infection, with three main pathogens responsible for the majority of cases:
- Coxsackievirus A16 (CV-A16) and Enterovirus 71 (EV-A71) are the traditional causative agents, with CV-A16 historically being the most common 1, 3
- Coxsackievirus A6 (CV-A6) has emerged as an increasingly important pathogen since approximately 2010, now causing more severe outbreaks worldwide and becoming the predominant strain in many regions 1, 2, 4
- Other minority enterovirus types can also cause HFMD, though less frequently 4, 5
Clinical Significance by Viral Type
The specific enterovirus type matters significantly for prognosis and clinical presentation:
Enterovirus 71 (EV-A71)
- Carries the highest risk for severe complications, including brainstem encephalitis, meningoencephalitis, acute flaccid paralysis, and pulmonary edema 1
- Responsible for large HFMD outbreaks with rare but severe cases of rhomboencephalitis, particularly in Asia and more recently in Europe 6, 1
- Children aged 6-12 months have the highest mortality risk 6
- Can cause neurogenic pulmonary edema on days 2-3 of illness, which may rapidly progress to fatal cardiorespiratory collapse 6
Coxsackievirus A6 (CV-A6)
- Presents with atypical features that distinguish it from classic HFMD, including widespread exanthema beyond classic distribution (involving the legs) and more severe skin manifestations requiring intensive skin care 1
- Associated with onychomadesis (nail shedding) occurring 1-2 months after fever onset 6, 1
- Patients often have higher fever and longer duration of disease than typical HFMD 2
- Has become a major cause of HFMD outbreaks in the United States and worldwide since 2010 2, 4
Coxsackievirus A16 (CV-A16)
- Typically causes classic HFMD presentation with oral herpes and rashes on hands and feet 3
- Generally associated with milder disease compared to EV-A71 1
Epidemiological Patterns
The enteroviral epidemiology of HFMD shows dynamic shifts over time:
- In Spain, CV-A16 was the only causative agent during most of 2010, but by late 2010 and throughout 2011, CV-A6 became predominant while CV-A16 was not detected 4
- Multiple pathogens can circulate simultaneously, with CV-A6 and CV-A16 both circulating in 2012 in Spain 4
- More than 20 types of enteroviruses can cause HFMD, making single-agent vaccine approaches comparatively inadequate 3, 7
Important Diagnostic Considerations
Vesicle fluid samples have the highest viral loads and are ideal for testing using reverse transcriptase PCR (RT-PCR) targeting the 5′ non-coding region 6, 1, 8
For neurological presentations:
- Respiratory specimens should always be collected, as viruses like EV-D68 and EV-A71 are often only detectable in respiratory tract specimens and/or stool, not in CSF 6
- Stool samples and respiratory samples can be used for diagnosis in addition to vesicle fluid 6, 1
Common Pitfalls to Avoid
- Do not assume all HFMD is benign: EV-A71 can cause severe neurological complications with rapid deterioration, particularly in children under 5 years 6, 3
- Do not rely solely on CSF testing for neurological presentations: respiratory and stool samples are essential as some enteroviruses are rarely detectable in CSF 6
- Watch for delayed complications: onychomadesis can occur 1-2 months after initial infection, particularly with CV-A6 6, 1
- Consider broader differential: while enteroviruses are the cause, other conditions like herpes simplex virus can present similarly and have specific antiviral treatments available 8