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Hand-foot-and-mouth Disease Caused by Coxsackievirus A6 on the Rise
Author(s)
Brooks David Kimmis, MD
Christopher Downing, MD
Stephen Tyring, MD, PhD

Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.24

Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.

Incidence of CVA6

Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.26 According to one study, “[n]early every Chinese city showed a sharp rise in [CVA6].”27

The incidence of CVA6 also has been increasing in other areas.28 In Spain, CVA6 overtook CVA16 as the dominant cause of HFMD during 2011 and 2012 outbreaks.29 From 2011 to 2012, there was a CVA6-associated HFMD outbreak in North America, with 63 cases reported to the Centers for Disease Control and Prevention (CDC), including 15 adult cases, with approximately 50% having been exposed to children with HFMD.9 In 2014, a Minnesota college with approximately 1000 students reported 9 suspected cases of HFMD to the Minnesota Department of Health. Coxsackievirus A6 was isolated, sequenced, and identified by the CDC in 5 of 9 patients (age range, 19–47 years).9

In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.7 Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.7

Presentation

Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1). Skin lesions often are painful and spread to a wider distribution than typical of HFMD, which can include the face, proximal extremities, lips, perianal and groin skin, scalp, and dorsal feet and hands (Figure 2). These areas are classically spared in the prototypical presentation of HFMD in children.2,6,24,30-33 Vesicles that are typically football shaped (Figure 3) are a diagnostic clue of the disease. After patients have recovered from the disease, they can have delayed-onset palmar and plantar desquamation that usually presents 1 to 3 weeks after the disease. Additionally, another postsyndrome finding is onychomadesis, or detachment of the nail plate from the nail matrix.6,34-37 This process likely occurs due to direct cytopathic effect to the nail matrix from the viral infection.24,37 Blistering may be severe and can form hemorrhagic bullae.24 Although cutaneous findings are more severe, neurologic involvement actually is more rare in the CVA6 strain compared to other viral strains known to cause HFMD, specifically EV71. One study found only 2.4% of 141 patients infected with CVA6 had central nervous system involvement, specifically aseptic meningitis or encephalitis.21,24

Figure1
Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).
Figure 1. Numerous vesicles on an erythematous base and erythematous papules on the dorsal and plantar feet.

Figure2
Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).
Figure 2. Ill-defined, erythematous, eroded plaque on the right proximal thigh, inguinal fold, and right scrotum.

Figure3
Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).
Figure 3. Classic football-shaped lesion of hand-foot-and-mouth disease.

In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.24

 

 

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

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.

References
  1. Galen WK. Cutaneous manifestations of enterovirus infections. In: Tyring SK, ed. Mucocutaneous Manifestations of Viral Diseases. New York, NY: Marcel Dekker; 2002:455-467.
  2. Ramirez-Fort M, Downing C, Doan H, et al. Coxsackievirus A6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature. J Clin Virol. 2014;60:381-386.
  3. Khetsuriani N, Lamonte-Fowlkes A, Oberst S, et al. Enterovirus surveillance—United States, 1970-2005. MMWR Surveill Summ. 2006;55:1-20.
  4. Yang F, Zhang T, Hu Y, et al. Survey of enterovirus infections from hand, foot and mouth disease outbreak in China, 2009. Virol J. 2011;8:508.
  5. Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341:929-935.
  6. Second J, Velter C, Calès S, et al. Clinicopathologic analysis of atypical hand, foot, and mouth disease in adult patients. J Am Acad Dermatol. 2016;76:722-729.
  7. Banta J, Lenz B, Pawlak M, et al. Notes from the field: outbreak of hand, foot, and mouth disease caused by coxsackievirus A6 among basic military trainees—Texas, 2015. MMWR Morb Mortal Wkly Rep. 2016;65.26:678-680.
  8. Bian L, Wang Y, Yao X, et al. Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide. Expert Rev Anti Infect Ther. 2015;13:1061-1071.
  9. Buttery VW, Kenyon C, Grunewald S, et al. Notes from the field: atypical presentations of hand, foot, and mouth disease caused by coxsackievirus A6—Minnesota, 2014. MMWR Morb Mortal Wkly Rep. 2015;64:805.
  10. Puenpa J, Chieochansin T, Linsuwanon P, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Thailand, 2012. Emerg Infect Dis. 2013;19:641-643.
  11. Flett K, Youngster I, Huang J, et al. Hand, foot, and mouth disease caused by coxsackievirus A6. Emerg Infect Dis. 2012;18:1702-1704.
  12. Centers for Disease Control and Prevention. Notes from the field: severe hand, foot, and mouth disease associated with coxsackievirus A6—Alabama, Connecticut, California, and Nevada, November 2011-February 2012. MMWR Morb Mortal Wkly Rep. 2012;61:213-214.
  13. Blomqvist S, Klemola P, Kaijalainen S, et al. Co-circulation of coxsackieviruses A6 and A10 in hand, foot and mouth disease outbreak in Finland. J Clin Virol. 2010;48:49-54.
  14. Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 2009;15:1485-1488.
  15. Zeng H, Lu J, Zheng H, et al. The epidemiological study of coxsackievirus A6 revealing hand, foot and mouth disease epidemic patterns in Guandong, China. Sci Rep. 2015;5:10550.
  16. Mirand A, Henquell C, Archimbaud C, et al. Outbreak of hand, foot and mouth disease/herpangina associated with coxsackievirus A6 andA10 infections in 2010, France: a large citywide, prospective observational study. Clin Microbiol Infect. 2012;18:E110-E118.
  17. Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346. 
  18. Fujimoto T, Iizuka S, Enomoto M, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Japan, 2011. Emerg Infect Dis. 2012;18:337-339.
  19. Bracho MA, Gonzalez-Candelas F, Valero A, et al. Enterovirus co-infections and onychomadesis after hand, foot, and mouth disease, Spain, 2008. Emerg Infect Dis. 2011;17:2223-2231.
  20. Gopalkrishna V, Patil PR, Patil GP, et al. Circulation of multiple enterovirus serotypes causing hand, foot and mouth disease in India. J Med Microbiol. 2012;61:420-425.
  21. Lo SH, Huang YC, Huang CG, et al. Clinical and epidemiologic features of coxsackievirus A6 infection in children in northern Taiwan between 2004 and 2009. J Microbiol Immunol Infect. 2011;44:252-257.
  22. Lu QB, Zhang XA, Wo Y, et al. Circulation of coxsackievirus A10 and A6 in hand-foot-mouth disease in China, 2009-2011. PLoS One. 2012;7:E52073.
  23. Wu Y, Yeo A, Phoon MC, et al. The largest outbreak of hand; foot and mouth disease in Singapore in 2008: the role of enterovirus 71 and coxsackievirus A strains. Int J Infect Dis. 2010;14:E1076-E1081.
  24. Ventarola D, Bordone L, Silverberg N. Update on hand-foot-and-mouth disease. Clin Dermatol. 2015;33:340-346.
  25. Li Y, Chang Z, Wu P, et al. Emerging enteroviruses causing hand, foot and mouth disease, China. 2010-2016. Emerg Infect Dis. 2018;24:1902-1906.
  26. Tan X, Li L, Zhang B, et al. Molecular epidemiology of coxsackievirus A6 associated with outbreaks of hand, foot, and mouth disease in Tianjin, China, in 2013. Arch Virol. 2015;160:1097-1104.
  27. Li Y, Bao H, Zhang X, et al. Epidemiological and genetic analysis concerning the non-enterovirus 71 and non-coxsackievirus A16 causative agents related to hand, foot and mouth disease in Anyang City, Henan Province, China, from 2011 to 2015. J Med Virol. 2017;89:1749-1758.
  28. Guan H, Wang J, Wang C, et al. Etiology of multiple non-EV71 and non-CVA16 enteroviruses associated with hand, foot, and mouth disease in Jinan, China, 2009-2013. PLoS One. 2015;10:E0142733.
  29. Cabrerizo M, Tarrago´ D, Muñoz-Almagro C, et al. Mollecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain. Clin Microbiol Infect. 2014;20:O150-O156.
  30. Lønnberg A, Elberling J, Fischer T, et al. Two cases of hand, foot, and mouth disease involving the scalp. Acta Derm Venereol. 2013;93:467-468.
  31. Lott JP, Liu K, Landry ML, et al. Atypical hand-foot-and-mouth disease associated with coxsackievirus A6 infection. J Am Acad Dermatol. 2013;69:736-741.
  32. Kaminska K, Martinetti G, Lucchini R, et al. Coxsackievirus A6 and hand, foot and mouth disease: three case reports of familial child-to-immunocompetent adult transmission and a literature review. Case Rep Dermatol. 2013;5:203-209.
  33. Shin JU, Oh SH, Lee JH. A case of hand-foot-mouth disease in an immunocompetent adult. Ann Dermatol. 2010;22:216-218.
  34. Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 2009;15:1485-1488.
  35. Feder HM, Bennett N, Modlin JF. Atypical hand, foot, and mouth disease: a vesiculobullous eruption caused by coxsackie virus A6. Lancet Infect Dis. 2014;14:83-86.
  36. Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346.
  37. Kim M, Kim B, Byun S, et al. Beau’s lines and onychomadesis after hand-foot-mouth disease. Clin Pediatr Dermatol. 2015;1:1.
  38. Mathes EF, Oza V, Frieden IJ, et al. “Eczema coxsackium” and unusual cutaneous findings in an enterovirus outbreak. Pediatrics. 2013;132:E149-E157.
  39. Lynch M, Sears A, Cookson H, et al. Disseminated coxsackievirus A6 affecting children with atopic dermatitis. Clin Exp Dermatol. 2015;40:525-528.
  40. Laga A, Shroba S, Hanna J. Atypical hand, foot and mouth disease in adults associated with coxsackievirus A6: a clinicopathologic study. J Cutan Pathol. 2016;43:940-945.
  41. Schmidt NJ, Ho HH, Lennette EH. Propagation and isolation of group A coxsackieviruses in RD cells. J Clin Microbiol. 1975;2:183-185.
  42. Oberste MS, Penaranda S, Rogers SL, et al. Comparative evaluation of Taqman real-time PCR and semi-nested VP1 PCR for detection of enteroviruses in clinical specimens. J Clin Virol. 2010;49:73-74. 
  43. Lee MK, Chan PK, Ho II, et al. Enterovirus infection among patients admitted to hospital in Hong Kong in 2010: epidemiology, clinical characteristics, and importance of molecular diagnosis. J Med Virol. 2013;85:1811-1817.
  44. Yee PTI, Laa Poh C. Impact of genetic changes, pathogenicity and antigenicity on enterovirus A71 vaccine development. Virology. 2017;506:121-129.
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Author and Disclosure Information

Dr. Kimmis is from the University of Missouri-Kansas City School of Medicine. Drs. Downing and Tyring are from the University of Texas Medical School at Houston.

The authors report no conflict of interest.

Correspondence: Brooks David Kimmis, MD, University of Missouri-Kansas City School of Medicine, 2411 Holmes St, Kansas City, MO 64108 ([email protected]).

Issue
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Page Number
353-356
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Clinical Review
Author(s)
Brooks David Kimmis, MD
Christopher Downing, MD
Stephen Tyring, MD, PhD
Author(s)
Brooks David Kimmis, MD
Christopher Downing, MD
Stephen Tyring, MD, PhD
Author and Disclosure Information

Dr. Kimmis is from the University of Missouri-Kansas City School of Medicine. Drs. Downing and Tyring are from the University of Texas Medical School at Houston.

The authors report no conflict of interest.

Correspondence: Brooks David Kimmis, MD, University of Missouri-Kansas City School of Medicine, 2411 Holmes St, Kansas City, MO 64108 ([email protected]).

Author and Disclosure Information

Dr. Kimmis is from the University of Missouri-Kansas City School of Medicine. Drs. Downing and Tyring are from the University of Texas Medical School at Houston.

The authors report no conflict of interest.

Correspondence: Brooks David Kimmis, MD, University of Missouri-Kansas City School of Medicine, 2411 Holmes St, Kansas City, MO 64108 ([email protected]).

Article PDF
CT102005353.PDF
Article PDF
CT102005353.PDF

Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.24

Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.

Incidence of CVA6

Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.26 According to one study, “[n]early every Chinese city showed a sharp rise in [CVA6].”27

The incidence of CVA6 also has been increasing in other areas.28 In Spain, CVA6 overtook CVA16 as the dominant cause of HFMD during 2011 and 2012 outbreaks.29 From 2011 to 2012, there was a CVA6-associated HFMD outbreak in North America, with 63 cases reported to the Centers for Disease Control and Prevention (CDC), including 15 adult cases, with approximately 50% having been exposed to children with HFMD.9 In 2014, a Minnesota college with approximately 1000 students reported 9 suspected cases of HFMD to the Minnesota Department of Health. Coxsackievirus A6 was isolated, sequenced, and identified by the CDC in 5 of 9 patients (age range, 19–47 years).9

In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.7 Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.7

Presentation

Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1). Skin lesions often are painful and spread to a wider distribution than typical of HFMD, which can include the face, proximal extremities, lips, perianal and groin skin, scalp, and dorsal feet and hands (Figure 2). These areas are classically spared in the prototypical presentation of HFMD in children.2,6,24,30-33 Vesicles that are typically football shaped (Figure 3) are a diagnostic clue of the disease. After patients have recovered from the disease, they can have delayed-onset palmar and plantar desquamation that usually presents 1 to 3 weeks after the disease. Additionally, another postsyndrome finding is onychomadesis, or detachment of the nail plate from the nail matrix.6,34-37 This process likely occurs due to direct cytopathic effect to the nail matrix from the viral infection.24,37 Blistering may be severe and can form hemorrhagic bullae.24 Although cutaneous findings are more severe, neurologic involvement actually is more rare in the CVA6 strain compared to other viral strains known to cause HFMD, specifically EV71. One study found only 2.4% of 141 patients infected with CVA6 had central nervous system involvement, specifically aseptic meningitis or encephalitis.21,24

Figure1
Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).
Figure 1. Numerous vesicles on an erythematous base and erythematous papules on the dorsal and plantar feet.

Figure2
Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).
Figure 2. Ill-defined, erythematous, eroded plaque on the right proximal thigh, inguinal fold, and right scrotum.

Figure3
Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).
Figure 3. Classic football-shaped lesion of hand-foot-and-mouth disease.

In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.24

 

 

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

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.

Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.24

Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.

Incidence of CVA6

Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.26 According to one study, “[n]early every Chinese city showed a sharp rise in [CVA6].”27

The incidence of CVA6 also has been increasing in other areas.28 In Spain, CVA6 overtook CVA16 as the dominant cause of HFMD during 2011 and 2012 outbreaks.29 From 2011 to 2012, there was a CVA6-associated HFMD outbreak in North America, with 63 cases reported to the Centers for Disease Control and Prevention (CDC), including 15 adult cases, with approximately 50% having been exposed to children with HFMD.9 In 2014, a Minnesota college with approximately 1000 students reported 9 suspected cases of HFMD to the Minnesota Department of Health. Coxsackievirus A6 was isolated, sequenced, and identified by the CDC in 5 of 9 patients (age range, 19–47 years).9

In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.7 Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.7

Presentation

Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1). Skin lesions often are painful and spread to a wider distribution than typical of HFMD, which can include the face, proximal extremities, lips, perianal and groin skin, scalp, and dorsal feet and hands (Figure 2). These areas are classically spared in the prototypical presentation of HFMD in children.2,6,24,30-33 Vesicles that are typically football shaped (Figure 3) are a diagnostic clue of the disease. After patients have recovered from the disease, they can have delayed-onset palmar and plantar desquamation that usually presents 1 to 3 weeks after the disease. Additionally, another postsyndrome finding is onychomadesis, or detachment of the nail plate from the nail matrix.6,34-37 This process likely occurs due to direct cytopathic effect to the nail matrix from the viral infection.24,37 Blistering may be severe and can form hemorrhagic bullae.24 Although cutaneous findings are more severe, neurologic involvement actually is more rare in the CVA6 strain compared to other viral strains known to cause HFMD, specifically EV71. One study found only 2.4% of 141 patients infected with CVA6 had central nervous system involvement, specifically aseptic meningitis or encephalitis.21,24

Figure1
Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).
Figure 1. Numerous vesicles on an erythematous base and erythematous papules on the dorsal and plantar feet.

Figure2
Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).
Figure 2. Ill-defined, erythematous, eroded plaque on the right proximal thigh, inguinal fold, and right scrotum.

Figure3
Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).
Figure 3. Classic football-shaped lesion of hand-foot-and-mouth disease.

In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.24

 

 

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

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.

References
  1. Galen WK. Cutaneous manifestations of enterovirus infections. In: Tyring SK, ed. Mucocutaneous Manifestations of Viral Diseases. New York, NY: Marcel Dekker; 2002:455-467.
  2. Ramirez-Fort M, Downing C, Doan H, et al. Coxsackievirus A6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature. J Clin Virol. 2014;60:381-386.
  3. Khetsuriani N, Lamonte-Fowlkes A, Oberst S, et al. Enterovirus surveillance—United States, 1970-2005. MMWR Surveill Summ. 2006;55:1-20.
  4. Yang F, Zhang T, Hu Y, et al. Survey of enterovirus infections from hand, foot and mouth disease outbreak in China, 2009. Virol J. 2011;8:508.
  5. Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341:929-935.
  6. Second J, Velter C, Calès S, et al. Clinicopathologic analysis of atypical hand, foot, and mouth disease in adult patients. J Am Acad Dermatol. 2016;76:722-729.
  7. Banta J, Lenz B, Pawlak M, et al. Notes from the field: outbreak of hand, foot, and mouth disease caused by coxsackievirus A6 among basic military trainees—Texas, 2015. MMWR Morb Mortal Wkly Rep. 2016;65.26:678-680.
  8. Bian L, Wang Y, Yao X, et al. Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide. Expert Rev Anti Infect Ther. 2015;13:1061-1071.
  9. Buttery VW, Kenyon C, Grunewald S, et al. Notes from the field: atypical presentations of hand, foot, and mouth disease caused by coxsackievirus A6—Minnesota, 2014. MMWR Morb Mortal Wkly Rep. 2015;64:805.
  10. Puenpa J, Chieochansin T, Linsuwanon P, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Thailand, 2012. Emerg Infect Dis. 2013;19:641-643.
  11. Flett K, Youngster I, Huang J, et al. Hand, foot, and mouth disease caused by coxsackievirus A6. Emerg Infect Dis. 2012;18:1702-1704.
  12. Centers for Disease Control and Prevention. Notes from the field: severe hand, foot, and mouth disease associated with coxsackievirus A6—Alabama, Connecticut, California, and Nevada, November 2011-February 2012. MMWR Morb Mortal Wkly Rep. 2012;61:213-214.
  13. Blomqvist S, Klemola P, Kaijalainen S, et al. Co-circulation of coxsackieviruses A6 and A10 in hand, foot and mouth disease outbreak in Finland. J Clin Virol. 2010;48:49-54.
  14. Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 2009;15:1485-1488.
  15. Zeng H, Lu J, Zheng H, et al. The epidemiological study of coxsackievirus A6 revealing hand, foot and mouth disease epidemic patterns in Guandong, China. Sci Rep. 2015;5:10550.
  16. Mirand A, Henquell C, Archimbaud C, et al. Outbreak of hand, foot and mouth disease/herpangina associated with coxsackievirus A6 andA10 infections in 2010, France: a large citywide, prospective observational study. Clin Microbiol Infect. 2012;18:E110-E118.
  17. Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346. 
  18. Fujimoto T, Iizuka S, Enomoto M, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Japan, 2011. Emerg Infect Dis. 2012;18:337-339.
  19. Bracho MA, Gonzalez-Candelas F, Valero A, et al. Enterovirus co-infections and onychomadesis after hand, foot, and mouth disease, Spain, 2008. Emerg Infect Dis. 2011;17:2223-2231.
  20. Gopalkrishna V, Patil PR, Patil GP, et al. Circulation of multiple enterovirus serotypes causing hand, foot and mouth disease in India. J Med Microbiol. 2012;61:420-425.
  21. Lo SH, Huang YC, Huang CG, et al. Clinical and epidemiologic features of coxsackievirus A6 infection in children in northern Taiwan between 2004 and 2009. J Microbiol Immunol Infect. 2011;44:252-257.
  22. Lu QB, Zhang XA, Wo Y, et al. Circulation of coxsackievirus A10 and A6 in hand-foot-mouth disease in China, 2009-2011. PLoS One. 2012;7:E52073.
  23. Wu Y, Yeo A, Phoon MC, et al. The largest outbreak of hand; foot and mouth disease in Singapore in 2008: the role of enterovirus 71 and coxsackievirus A strains. Int J Infect Dis. 2010;14:E1076-E1081.
  24. Ventarola D, Bordone L, Silverberg N. Update on hand-foot-and-mouth disease. Clin Dermatol. 2015;33:340-346.
  25. Li Y, Chang Z, Wu P, et al. Emerging enteroviruses causing hand, foot and mouth disease, China. 2010-2016. Emerg Infect Dis. 2018;24:1902-1906.
  26. Tan X, Li L, Zhang B, et al. Molecular epidemiology of coxsackievirus A6 associated with outbreaks of hand, foot, and mouth disease in Tianjin, China, in 2013. Arch Virol. 2015;160:1097-1104.
  27. Li Y, Bao H, Zhang X, et al. Epidemiological and genetic analysis concerning the non-enterovirus 71 and non-coxsackievirus A16 causative agents related to hand, foot and mouth disease in Anyang City, Henan Province, China, from 2011 to 2015. J Med Virol. 2017;89:1749-1758.
  28. Guan H, Wang J, Wang C, et al. Etiology of multiple non-EV71 and non-CVA16 enteroviruses associated with hand, foot, and mouth disease in Jinan, China, 2009-2013. PLoS One. 2015;10:E0142733.
  29. Cabrerizo M, Tarrago´ D, Muñoz-Almagro C, et al. Mollecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain. Clin Microbiol Infect. 2014;20:O150-O156.
  30. Lønnberg A, Elberling J, Fischer T, et al. Two cases of hand, foot, and mouth disease involving the scalp. Acta Derm Venereol. 2013;93:467-468.
  31. Lott JP, Liu K, Landry ML, et al. Atypical hand-foot-and-mouth disease associated with coxsackievirus A6 infection. J Am Acad Dermatol. 2013;69:736-741.
  32. Kaminska K, Martinetti G, Lucchini R, et al. Coxsackievirus A6 and hand, foot and mouth disease: three case reports of familial child-to-immunocompetent adult transmission and a literature review. Case Rep Dermatol. 2013;5:203-209.
  33. Shin JU, Oh SH, Lee JH. A case of hand-foot-mouth disease in an immunocompetent adult. Ann Dermatol. 2010;22:216-218.
  34. Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 2009;15:1485-1488.
  35. Feder HM, Bennett N, Modlin JF. Atypical hand, foot, and mouth disease: a vesiculobullous eruption caused by coxsackie virus A6. Lancet Infect Dis. 2014;14:83-86.
  36. Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346.
  37. Kim M, Kim B, Byun S, et al. Beau’s lines and onychomadesis after hand-foot-mouth disease. Clin Pediatr Dermatol. 2015;1:1.
  38. Mathes EF, Oza V, Frieden IJ, et al. “Eczema coxsackium” and unusual cutaneous findings in an enterovirus outbreak. Pediatrics. 2013;132:E149-E157.
  39. Lynch M, Sears A, Cookson H, et al. Disseminated coxsackievirus A6 affecting children with atopic dermatitis. Clin Exp Dermatol. 2015;40:525-528.
  40. Laga A, Shroba S, Hanna J. Atypical hand, foot and mouth disease in adults associated with coxsackievirus A6: a clinicopathologic study. J Cutan Pathol. 2016;43:940-945.
  41. Schmidt NJ, Ho HH, Lennette EH. Propagation and isolation of group A coxsackieviruses in RD cells. J Clin Microbiol. 1975;2:183-185.
  42. Oberste MS, Penaranda S, Rogers SL, et al. Comparative evaluation of Taqman real-time PCR and semi-nested VP1 PCR for detection of enteroviruses in clinical specimens. J Clin Virol. 2010;49:73-74. 
  43. Lee MK, Chan PK, Ho II, et al. Enterovirus infection among patients admitted to hospital in Hong Kong in 2010: epidemiology, clinical characteristics, and importance of molecular diagnosis. J Med Virol. 2013;85:1811-1817.
  44. Yee PTI, Laa Poh C. Impact of genetic changes, pathogenicity and antigenicity on enterovirus A71 vaccine development. Virology. 2017;506:121-129.
References
  1. Galen WK. Cutaneous manifestations of enterovirus infections. In: Tyring SK, ed. Mucocutaneous Manifestations of Viral Diseases. New York, NY: Marcel Dekker; 2002:455-467.
  2. Ramirez-Fort M, Downing C, Doan H, et al. Coxsackievirus A6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature. J Clin Virol. 2014;60:381-386.
  3. Khetsuriani N, Lamonte-Fowlkes A, Oberst S, et al. Enterovirus surveillance—United States, 1970-2005. MMWR Surveill Summ. 2006;55:1-20.
  4. Yang F, Zhang T, Hu Y, et al. Survey of enterovirus infections from hand, foot and mouth disease outbreak in China, 2009. Virol J. 2011;8:508.
  5. Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341:929-935.
  6. Second J, Velter C, Calès S, et al. Clinicopathologic analysis of atypical hand, foot, and mouth disease in adult patients. J Am Acad Dermatol. 2016;76:722-729.
  7. Banta J, Lenz B, Pawlak M, et al. Notes from the field: outbreak of hand, foot, and mouth disease caused by coxsackievirus A6 among basic military trainees—Texas, 2015. MMWR Morb Mortal Wkly Rep. 2016;65.26:678-680.
  8. Bian L, Wang Y, Yao X, et al. Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide. Expert Rev Anti Infect Ther. 2015;13:1061-1071.
  9. Buttery VW, Kenyon C, Grunewald S, et al. Notes from the field: atypical presentations of hand, foot, and mouth disease caused by coxsackievirus A6—Minnesota, 2014. MMWR Morb Mortal Wkly Rep. 2015;64:805.
  10. Puenpa J, Chieochansin T, Linsuwanon P, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Thailand, 2012. Emerg Infect Dis. 2013;19:641-643.
  11. Flett K, Youngster I, Huang J, et al. Hand, foot, and mouth disease caused by coxsackievirus A6. Emerg Infect Dis. 2012;18:1702-1704.
  12. Centers for Disease Control and Prevention. Notes from the field: severe hand, foot, and mouth disease associated with coxsackievirus A6—Alabama, Connecticut, California, and Nevada, November 2011-February 2012. MMWR Morb Mortal Wkly Rep. 2012;61:213-214.
  13. Blomqvist S, Klemola P, Kaijalainen S, et al. Co-circulation of coxsackieviruses A6 and A10 in hand, foot and mouth disease outbreak in Finland. J Clin Virol. 2010;48:49-54.
  14. Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 2009;15:1485-1488.
  15. Zeng H, Lu J, Zheng H, et al. The epidemiological study of coxsackievirus A6 revealing hand, foot and mouth disease epidemic patterns in Guandong, China. Sci Rep. 2015;5:10550.
  16. Mirand A, Henquell C, Archimbaud C, et al. Outbreak of hand, foot and mouth disease/herpangina associated with coxsackievirus A6 andA10 infections in 2010, France: a large citywide, prospective observational study. Clin Microbiol Infect. 2012;18:E110-E118.
  17. Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346. 
  18. Fujimoto T, Iizuka S, Enomoto M, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Japan, 2011. Emerg Infect Dis. 2012;18:337-339.
  19. Bracho MA, Gonzalez-Candelas F, Valero A, et al. Enterovirus co-infections and onychomadesis after hand, foot, and mouth disease, Spain, 2008. Emerg Infect Dis. 2011;17:2223-2231.
  20. Gopalkrishna V, Patil PR, Patil GP, et al. Circulation of multiple enterovirus serotypes causing hand, foot and mouth disease in India. J Med Microbiol. 2012;61:420-425.
  21. Lo SH, Huang YC, Huang CG, et al. Clinical and epidemiologic features of coxsackievirus A6 infection in children in northern Taiwan between 2004 and 2009. J Microbiol Immunol Infect. 2011;44:252-257.
  22. Lu QB, Zhang XA, Wo Y, et al. Circulation of coxsackievirus A10 and A6 in hand-foot-mouth disease in China, 2009-2011. PLoS One. 2012;7:E52073.
  23. Wu Y, Yeo A, Phoon MC, et al. The largest outbreak of hand; foot and mouth disease in Singapore in 2008: the role of enterovirus 71 and coxsackievirus A strains. Int J Infect Dis. 2010;14:E1076-E1081.
  24. Ventarola D, Bordone L, Silverberg N. Update on hand-foot-and-mouth disease. Clin Dermatol. 2015;33:340-346.
  25. Li Y, Chang Z, Wu P, et al. Emerging enteroviruses causing hand, foot and mouth disease, China. 2010-2016. Emerg Infect Dis. 2018;24:1902-1906.
  26. Tan X, Li L, Zhang B, et al. Molecular epidemiology of coxsackievirus A6 associated with outbreaks of hand, foot, and mouth disease in Tianjin, China, in 2013. Arch Virol. 2015;160:1097-1104.
  27. Li Y, Bao H, Zhang X, et al. Epidemiological and genetic analysis concerning the non-enterovirus 71 and non-coxsackievirus A16 causative agents related to hand, foot and mouth disease in Anyang City, Henan Province, China, from 2011 to 2015. J Med Virol. 2017;89:1749-1758.
  28. Guan H, Wang J, Wang C, et al. Etiology of multiple non-EV71 and non-CVA16 enteroviruses associated with hand, foot, and mouth disease in Jinan, China, 2009-2013. PLoS One. 2015;10:E0142733.
  29. Cabrerizo M, Tarrago´ D, Muñoz-Almagro C, et al. Mollecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain. Clin Microbiol Infect. 2014;20:O150-O156.
  30. Lønnberg A, Elberling J, Fischer T, et al. Two cases of hand, foot, and mouth disease involving the scalp. Acta Derm Venereol. 2013;93:467-468.
  31. Lott JP, Liu K, Landry ML, et al. Atypical hand-foot-and-mouth disease associated with coxsackievirus A6 infection. J Am Acad Dermatol. 2013;69:736-741.
  32. Kaminska K, Martinetti G, Lucchini R, et al. Coxsackievirus A6 and hand, foot and mouth disease: three case reports of familial child-to-immunocompetent adult transmission and a literature review. Case Rep Dermatol. 2013;5:203-209.
  33. Shin JU, Oh SH, Lee JH. A case of hand-foot-mouth disease in an immunocompetent adult. Ann Dermatol. 2010;22:216-218.
  34. Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 2009;15:1485-1488.
  35. Feder HM, Bennett N, Modlin JF. Atypical hand, foot, and mouth disease: a vesiculobullous eruption caused by coxsackie virus A6. Lancet Infect Dis. 2014;14:83-86.
  36. Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346.
  37. Kim M, Kim B, Byun S, et al. Beau’s lines and onychomadesis after hand-foot-mouth disease. Clin Pediatr Dermatol. 2015;1:1.
  38. Mathes EF, Oza V, Frieden IJ, et al. “Eczema coxsackium” and unusual cutaneous findings in an enterovirus outbreak. Pediatrics. 2013;132:E149-E157.
  39. Lynch M, Sears A, Cookson H, et al. Disseminated coxsackievirus A6 affecting children with atopic dermatitis. Clin Exp Dermatol. 2015;40:525-528.
  40. Laga A, Shroba S, Hanna J. Atypical hand, foot and mouth disease in adults associated with coxsackievirus A6: a clinicopathologic study. J Cutan Pathol. 2016;43:940-945.
  41. Schmidt NJ, Ho HH, Lennette EH. Propagation and isolation of group A coxsackieviruses in RD cells. J Clin Microbiol. 1975;2:183-185.
  42. Oberste MS, Penaranda S, Rogers SL, et al. Comparative evaluation of Taqman real-time PCR and semi-nested VP1 PCR for detection of enteroviruses in clinical specimens. J Clin Virol. 2010;49:73-74. 
  43. Lee MK, Chan PK, Ho II, et al. Enterovirus infection among patients admitted to hospital in Hong Kong in 2010: epidemiology, clinical characteristics, and importance of molecular diagnosis. J Med Virol. 2013;85:1811-1817.
  44. Yee PTI, Laa Poh C. Impact of genetic changes, pathogenicity and antigenicity on enterovirus A71 vaccine development. Virology. 2017;506:121-129.
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Hand-foot-and-mouth Disease Caused by Coxsackievirus A6 on the Rise
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Hand-foot-and-mouth Disease Caused by Coxsackievirus A6 on the Rise
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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.
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