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Review
Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide Expert Rev. Anti Infect. Ther. Early online, 1–11 (2015)
Lianlian Bian, Yiping Wang, Xin Yao, Qunying Mao, Miao Xu and Zhenglun Liang* National Institutes for Food and Drug Control, Beijing 100050, China *Author for correspondence: Tel.: +86 10 6709 5669 Fax: +86 10 6709 5669 [email protected]
Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the predominant pathogens causing outbreaks of hand, foot and mouth disease (HFMD) worldwide. Other human enterovirus A (HEV-A) serotypes tend to cause only sporadic HFMD cases. However, since a HFMD caused by coxsackievirus A6 broke out in Finland in 2008, CA6 has been identified as the responsible pathogen for a series of HFMD outbreaks in Europe, North America and Asia. Because of the severity of the clinical manifestations and the underestimated public health burden, the epidemic of CA6-associated HFMD presents a new challenge to the control of HFMD. This article reviewed the epidemic characteristics, molecular epidemiology, clinical features and laboratory diagnosis of CA6 infection. The genetic evolution of CA6 strains associated with HFMD was also analyzed. It indicated that the development of a multivalent vaccine combining EV71, CA16 and CA6 is an urgent necessity to control HFMD. KEYWORDS: coxsackievirus A16 . coxsackievirus A6 . enterovirus 71 . hand, foot and mouth disease . vaccine
Hand, foot and mouth disease (HFMD) has become a significant public health concern worldwide since 1998, especially in the Western Pacific Region [1–3]. Since mainland China incorporated HFMD into the National Notifiable Diseases Surveillance System (NNDSS) in 2008, 11,748,976 HFMD cases and 3213 deaths had been reported since October 2014 [4]. More than 90% of HFMD cases are caused by Human enterovirus A (HEV-A) pathogens [5]. HEV-A comprises coxsackievirus A (CA) 2–8, 10, 12, 14, 16 and enterovirus 71 (EV71). EV71 and CA16 are the leading causes of HFMD outbreaks [6,7]; however, other HEV-A pathogens have been found in sporadic cases of HFMD [1,8]. One HEV-A pathogen, CA6, caused a HFMD outbreak in Finland in 2008 and then circulated in France, Spain and other European countries from 2009 to 2011 [5,9,10]. In Asia, CA6 has become one of the main pathogens responsible for causing HFMD outbreaks and CA6 has replaced EV71 and CA16 as the primary pathogen causing HFMD since 2009. CA6 was responsible for HFMD outbreaks in Singapore in 2009 [11], Taiwan in 2009– 2010 [12], Japan in 2011 [13], Thailand in informahealthcare.com
10.1586/14787210.2015.1058156
2012 [14] and mainland China in 2013 [15–21]. In North America, CA6-associated HFMD outbreaks have been reported in the USA [22] and Cuba [23] from 2011 to 2013. The CA6 strain that caused the HFMD outbreak in Finland in 2008 has become the predominant pathogen for the subsequent HFMD outbreaks in other countries (TABLE 1) [8,24]. CA6-associated HFMD has several clinical features that differ from classic HFMD caused by EV71 or CA16. The predominant clinical features of CA6-associated HFMD are atypical herpes and onychomadesis, a shedding of the nails [12,13]. CA6-associated HFMD is also characterized by high frequent onset in winter and high morbidity in adults. CA6 can often cause herpangina (HA), an illness exhibiting painful mouth blisters, but HA is not included in the data reported to NNDSS for HFMD in many countries. Therefore, the public health burden of diseases caused by CA6 infection may be underestimated. EV71 and CA16 have received much attention as the major pathogens responsible for causing HFMD. Monovalent EV71 vaccines from five manufactures have entered clinical trials.
2015 Informa UK Ltd
ISSN 1478-7210
1
Review
Bian, Wang, Yao, Mao, Xu & Liang
Table 1. Outbreaks of CA6-associated hand, foot and mouth disease worldwide. Study (year)
Countries/regions
Year
Age (average)
Main pathogens
Ref.
Blomqvist et al. (2010)
Finland
2008
2.5 months to 70 years (6 years)
CA6: 70.9% (83/117); CA10: 28.2% (33/117)
[41]
Mirand et al. (2012)
France
2010
5 weeks to 14 years (2.4 years)
CA6: 28.4% (40/141); CA10: 39.9% (56/141); CA16: 17.5% (25/141)
[5]
Montes et al. (2013)
Spain
2011
12–36 months (
Review
Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide Expert Rev. Anti Infect. Ther. Early online, 1–11 (2015)
Lianlian Bian, Yiping Wang, Xin Yao, Qunying Mao, Miao Xu and Zhenglun Liang* National Institutes for Food and Drug Control, Beijing 100050, China *Author for correspondence: Tel.: +86 10 6709 5669 Fax: +86 10 6709 5669 [email protected]
Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the predominant pathogens causing outbreaks of hand, foot and mouth disease (HFMD) worldwide. Other human enterovirus A (HEV-A) serotypes tend to cause only sporadic HFMD cases. However, since a HFMD caused by coxsackievirus A6 broke out in Finland in 2008, CA6 has been identified as the responsible pathogen for a series of HFMD outbreaks in Europe, North America and Asia. Because of the severity of the clinical manifestations and the underestimated public health burden, the epidemic of CA6-associated HFMD presents a new challenge to the control of HFMD. This article reviewed the epidemic characteristics, molecular epidemiology, clinical features and laboratory diagnosis of CA6 infection. The genetic evolution of CA6 strains associated with HFMD was also analyzed. It indicated that the development of a multivalent vaccine combining EV71, CA16 and CA6 is an urgent necessity to control HFMD. KEYWORDS: coxsackievirus A16 . coxsackievirus A6 . enterovirus 71 . hand, foot and mouth disease . vaccine
Hand, foot and mouth disease (HFMD) has become a significant public health concern worldwide since 1998, especially in the Western Pacific Region [1–3]. Since mainland China incorporated HFMD into the National Notifiable Diseases Surveillance System (NNDSS) in 2008, 11,748,976 HFMD cases and 3213 deaths had been reported since October 2014 [4]. More than 90% of HFMD cases are caused by Human enterovirus A (HEV-A) pathogens [5]. HEV-A comprises coxsackievirus A (CA) 2–8, 10, 12, 14, 16 and enterovirus 71 (EV71). EV71 and CA16 are the leading causes of HFMD outbreaks [6,7]; however, other HEV-A pathogens have been found in sporadic cases of HFMD [1,8]. One HEV-A pathogen, CA6, caused a HFMD outbreak in Finland in 2008 and then circulated in France, Spain and other European countries from 2009 to 2011 [5,9,10]. In Asia, CA6 has become one of the main pathogens responsible for causing HFMD outbreaks and CA6 has replaced EV71 and CA16 as the primary pathogen causing HFMD since 2009. CA6 was responsible for HFMD outbreaks in Singapore in 2009 [11], Taiwan in 2009– 2010 [12], Japan in 2011 [13], Thailand in informahealthcare.com
10.1586/14787210.2015.1058156
2012 [14] and mainland China in 2013 [15–21]. In North America, CA6-associated HFMD outbreaks have been reported in the USA [22] and Cuba [23] from 2011 to 2013. The CA6 strain that caused the HFMD outbreak in Finland in 2008 has become the predominant pathogen for the subsequent HFMD outbreaks in other countries (TABLE 1) [8,24]. CA6-associated HFMD has several clinical features that differ from classic HFMD caused by EV71 or CA16. The predominant clinical features of CA6-associated HFMD are atypical herpes and onychomadesis, a shedding of the nails [12,13]. CA6-associated HFMD is also characterized by high frequent onset in winter and high morbidity in adults. CA6 can often cause herpangina (HA), an illness exhibiting painful mouth blisters, but HA is not included in the data reported to NNDSS for HFMD in many countries. Therefore, the public health burden of diseases caused by CA6 infection may be underestimated. EV71 and CA16 have received much attention as the major pathogens responsible for causing HFMD. Monovalent EV71 vaccines from five manufactures have entered clinical trials.
2015 Informa UK Ltd
ISSN 1478-7210
1
Review
Bian, Wang, Yao, Mao, Xu & Liang
Table 1. Outbreaks of CA6-associated hand, foot and mouth disease worldwide. Study (year)
Countries/regions
Year
Age (average)
Main pathogens
Ref.
Blomqvist et al. (2010)
Finland
2008
2.5 months to 70 years (6 years)
CA6: 70.9% (83/117); CA10: 28.2% (33/117)
[41]
Mirand et al. (2012)
France
2010
5 weeks to 14 years (2.4 years)
CA6: 28.4% (40/141); CA10: 39.9% (56/141); CA16: 17.5% (25/141)
[5]
Montes et al. (2013)
Spain
2011
12–36 months (
