Hand-foot-and-mouth Disease Caused by Coxsackievirus A6 on the Rise
Hand-foot-and-mouth disease (HFMD) is a viral illness caused most commonly by coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease mainly affects pediatric populations younger than 5 years and is characterized by lesions of the oral mucosa, palms, and soles, lasting for 7 to 10 days. In recent years, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide. This strain also has been associated with adult HFMD. It affects broader demographics and causes more severe disease with unique findings compared to typical viral strands. Patients often have higher fever and longer duration of disease than typical HFMD and often present with more severe skin manifestations, spreading to a wider distribution than typical HFMD. We review the increasing prevalence of this viral illness to better characterize its clinical presentation.
Practice Points
- Coxsackievirus A6 is an increasingly more common cause of hand-foot-and-mouth disease (HFMD), often with atypical presentation, more severe disease, and association with HFMD in adults.
- Coxsackievirus A6 has become a major cause of HFMD outbreak in the United States and worldwide.
Clinical Diagnosis
Because HFMD is uncommon and atypical in adults, skin biopsies may be used in the initial workup and evaluation of patients. It is important to understand the histologic features associated with HFMD, including spongiosis with exocytosis of neutrophils as well as keratinocyte necrosis and pallor with associated shadow cells.6 In one series, the most extensively involved areas of keratinocyte necrosis were the stratum granulosum and upper half of the stratum spinosum.40 In the dermis, vascular involvement may be present on a spectrum with the extravasation of red blood cells and leukocytoclasis or true leukocytoclastic vasculitis.6,40 Vesicular lesions show severe dermal edema and inflammatory infiltrate.6,41 CD3+ and CD8+ lymphocytes predominate. Cytotoxic T lymphocytes are present and express granzyme B and granulysin, both important mediators of apoptosis in virally infected keratinocytes.6
Adult HFMD primarily is a clinical diagnosis, and histopathologic analysis can be a useful tool in certain cases. Coxsackievirus A6 does not grow well on culture and is not detected by standard serologic testing laboratories, necessitating the use of quantitative RT-PCR analysis.41,42 In one study, culture was able to detect only 14% to 16% of samples that tested positive by quantitative RT-PCR.43 This form of PCR identifies viral subtype through amplification of enterovirus viral protein 1 capsid gene sequence.24 Unfortunately, this testing often is not offered in most readily available laboratories and often necessitates being sent out to more well-equipped laboratories.2,24
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Treatment
Hand-foot-and-mouth disease is a self-limited illness and requires only supportive care with a focus on hydration and pain management. Lesions heal without scarring but may leave notable postinflammatory pigment alteration that may last months to years, depending on extent of disease and skin type. Secondarily infected individuals should be treated with appropriate antibiotics or antivirals depending on the infectious agent. Hand hygiene is of great importance, and hospitalized patients should be put on strict contact precautions. It also is important to isolate patients from vulnerable individuals, especially pregnant women, as coxsackievirus has been linked to intrauterine infections and loss of pregnancy.24
Genetic Analysis
Genetic studies of the virus have suggested that nonstructural genes may be playing an interesting role in clinical phenotypes and outcomes of CVA6 infection.44 These genetic studies also are being implemented into the understanding of the virus’ evolution as well as the construction of vaccinations.27,44
Conclusion
With the increasing prevalence of CVA6-associated HFMD, it is important to understand the clinical presentation and histologic findings associated with this atypical presentation of the disease as well as the changing epidemiology of the viral strains causing HFMD.
