The Topic of This Month Vol. 33, No. 3 (No. 385)

Hand, foot and mouth disease in Japan, 2002-2011
(IASR 33: 55-56, March 2012)

Hand, foot and mouth disease (HFMD) is characterized by vesicular exanthema of the oral mucosa and peripheral extremities.  It predominately affects young children during the summer season.  Common enterovirus isolates from HFMD cases are coxsackievirus A type 16 (CVA16) and enterovirus 71 (EV71), both belonging to human enterovirus species A (IASR 19: 150-151, 1998 & 25: 224-225, 2004).  The year 2011 experienced the largest HFMD epidemic since the start of National Epidemiological Surveillance of Infectious Diseases (NESID) (July 1981).  The most frequent type isolated from the 2011 epidemic was coxsackievirus A type 6 (CVA6), which had ever been one of the main causative agents of herpangina.  This special issue summarizes incidence of HFMD and virus isolation in the past 10 years.

Trends of HFMD epidemics and virus isolation/detection: Weekly reports of NESID (Fig. 1) demonstrate that the peak of HFMD epidemic occurs in the summer.  However, epidemics may also occur in the autumn and winter.

The monthly reports from prefectural and municipal public health institutes (PHIs) on EV71, CVA16, CVA10 and CVA6 (Fig. 2) indicate that there have been three large HFMD epidemics since 2002, the first in 2003 (total 172,659 cases; 56.78 per sentinel), the second in 2010 (total 151,021; 49.87 per sentinel), and the last in 2011 (total 347,362; 110.91 per sentinel).  The former two epidemics were caused by EV71 and the last one, which was the largest, by CVA6 and CVA16.  EV71 epidemics have occurred at 3-4 year intervals since 1994 (IASR 25: 224-225, 2004).

As for age distribution in 2002-2011 (Fig. 3), similarly as in the preceding years, ninety percent of the reported cases were under five.  However, exact number of adult cases is obscure as the present surveillance is based on pediatric sentinels.  Most EV71, CVA16, CVA10 and CVA6 isolates were from children under seven years (Fig. 4).  Among EV71-positive cases in the 2010 epidemic, cases with aseptic meningitis were found in two peak age groups, 0 year and 3-5 years (61/880).  In the 2011 epidemic, aseptic meningitis cases were found only in seven among 1,187 CVA6-positive cases (IASR 32: 228-230, 2011), though severe skin symptoms were reported from the adult CVA6-positive cases (IASR 32: 231, 2011).  No aseptic meningitis case was reported among 528 CVA16-positive cases in 2011.

Data on the isolation frequencies by prefecture of EV71, CVA16, CVA10 and CVA6 in 2011 are shown in Fig. 5 together with the data of EV71 in 2010.  In 2011, more than one type among CVA16, CVA10 and CVA6 caused the HFMD epidemic in various parts of Japan (IASR 32: 232-233, 2011), and some patients experienced multiple infections with different enterovirus serotypes (see p. 59 of this issue).  Interestingly, prefectures that reported EV71 in 2010 reported no EV71 in 2011.

Complications of HFMD: Since the late 1990's, a large number of severe, occasionally fatal, central nervous complications associated with large scale HFMD outbreaks have been reported from the East Asia and nearby regions.  More recently, many fatal cases have been reported from China (2008-2010; 905 fatal cases in 2010) and Vietnam (2011) (   Most such severe cases are related to EV71-associated acute encephalitis and other central nervous system complications (IASR 30: 9-10, 2009).  Taiwan, China and other Asian countries are now developing EV71 vaccines for clinical use in near future (see p. 65 of this issue).

Japan has not yet experienced large-scale HFMD epidemic accompanying high frequency of fatal cases, though sudden deaths associated with severe EV71 infection have been reported sporadically (IASR 19: 55, 1998).  The questionnaire-based studies (2000-2002) indicated an increase of severe cases of HFMD when the epidemic was caused by EV71 (2000) (Pedriatr International 52: 203-207, 2010).  For epidemiological comparison with other countries, a nationwide investigation on complications associated with the HFMD epidemic mainly due to EV71 in 2010 has been undertaken using WHO's case definitions ( (see p. 63 of this issue).

CVA6, together with other CVAs, had been a major cause of herpangina; since the 2009 HFMD epidemic, however, it started to be isolated more frequently from HFMD (Fig. 2).  Clinical picture of CVA6-associated HFMD is characterized by larger blisters, which extend to legs and buttocks (IASR 32: 230-231, 2011).  Cases of onychomadesis has been reported after recovery from HFMD (see pp. 59 and 62 of this issue and Emerg Infect Dis 18: 337-339, 2012), and CVA6 was detected from the nail that dropped off (IASR 32: 339-340, 2011).  CVA6-related HFMD and onychomadesis had been reported in Europe and Asia since 2008, and molecular analysis revealed phylogenetic relatedness of the above Japanese isolates to the recent European isolates (see p. 60 of this issue).  Future evolution of CVA6's pathogenicity including onychomadesis should be followed.

Laboratory diagnosis of HFMD: Laboratory diagnosis consists of virus isolation, viral gene detection and typing (see pp. 57 and 58 of this issue), using throat swab or stool specimens during the clinical phase.  The major causative agents of HFMD, EV71 and CVA16 can be isolated by using RD-A, Vero and other cultured cell lines.  The isolates are identified by neutralization tests or by sequencing analysis.  As some CVAs do not grow well in cultured cells (IASR 32: 196, 2011), isolation by suckling mice has been conventionally used (IASR 32: 195-196, 2011).  While CVA6 reported in 2011 was directly detected/identified from the clinical specimens by using CODEHOP VP1 RT-seminested PCR (IASR 30: 12-13, 2009), successful isolations of the virus by using RD-A cell cultures or suckling mouse method have been reported (see pp. 57, 58 and 59 of this issue).  The information on virus isolation trends is crucial for efficient laboratory diagnosis of HFMD-related enteroviruses (see p. 61 of this issue).

Infectious agent surveillance on HFMD in Japan is conducted by PHIs and National Institute of Infectious Diseases through collaboration of Enterovirus Reference Centers, which should be further fortified by strengthening of laboratory capacity as regards virus isolation, culture and other necessary practices.

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