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The topic of This Month Vol.38 No.10(No.452)

Hand, foot, and mouth disease and herpangina, 2007 to September 2017 (week 38), Japan

(IASR Vol. 38 p191-193: October, 2017)

Hand, foot, and mouth disease (HFMD) and herpangina are pediatric enteroviral diseases that often occur in the summer.  Both are category V infectious diseases under the Infectious Diseases Control Law, notifiable based on clinical diagnosis from ~3,000 pediatric sentinel sites.  Reporting requires the following clinical manifestations: “2-5mm-sized blisters appearing on the palm, plantar, dorsum of foot or oral mucosa” that “heal without crust formation” for HFMD, and “sudden onset of high fever” and “vesicular rash, ulcers or reddening of the uvula” for herpangina.  Causative agents are mostly viruses belonging to Enterovirus A.

Trends in notifications of patients and detection of viruses: For both HFMD and herpangina, notifications of patient cases peaked in the summer. For HFMD, large and small epidemic years alternated yearly since 2011 (large epidemic years occurred in 2011, 2013, 2015 and 2017) (Fig. 1). For herpangina, the magnitude of annual fluctuations was smaller (Fig. 2).

Among the reported cases, both for HFMD and herpangina, 90% of the patients were under 5 years of age (Fig. 3 and 4, respectively). As both are monitored via pediatric sentinel sites, the frequency of disease occurrence among adults is unknown. Findings from HFMD surveillance abroad have similarly found that the annualized HFMD incidence among children 6 months-5 years far exceeded those of other age groups, with particularly low levels among those ≥15 years of age (Lancet Infect Dis 14: 308-318, 2014).

Annual trends in detection of Enterovirus A by prefectural and municipal public health institutes (PHIs) from 2007-2017 are shown in Fig. 5. From HFMD cases, coxsackievirus (CV)-A6, CV-A16 and enterovirus (EV)-A71 were detected; since 2011, CV-A6 was associated with large scale epidemics (Fig. 1 and 5). While EV-A71 was detected in relatively large numbers in 2010 and 2013, it has not been associated with large epidemics since 2014. From herpangina cases, the following were detected, in descending order of frequency: CV-A4, CV-A6, CV-A10, CV-A2, CV-A5 and CV-A8; the predominant type circulating was found to vary yearly (https://www.niid.go.jp/niid/ja/iasr-sp/510-graphs/4892-iasrgnatsu.html).

For past reports on HFMD and herpangina, please visit the following: HFMD (IASR 33: 55-56, 2012) and herpangina (IASR 26: 235-236, 2005).

Laboratory diagnosis: Laboratory diagnosis consists of virus isolation and virus genome detection using throat swab or stool specimens during the clinically symptomatic phase. Using multiple cell lines, such as RD cells and Vero cells, has been known to increase virus isolation efficiency for both HFMD and herpangina. As virus isolation efficiency was particularly low for herpangina cases, some PHIs have been conducting virus isolation using suckling mice (see pp. 200 & 202 of this issue).

Recently, for more rapid and simpler methods and to also overcome the low isolation efficiency in cultured cells, viral genome detection directly from clinical specimens has been increasing. For identification of enterovirus type, amplification of the partial sequences of the VP4-VP2 region and/or VP1 regions (e.g., CODEHOP RT-semi-nested PCR) has been used (see Laboratory Manual for HFMD and herpangina). For routine testing, amplification of the VP1 region, where there is high correlation with enterovirus serotypes, is preferable (IASR 30: 12-13, 2009). Since the amendment of the Infectious Diseases Control Law in 2014, quality control and quality assurance for enterovirus laboratory testing have been implemented (see p. 199 of this issue).

Characteristics of HFMD in recent years and central nervous system complications: Although CV-A6 had been detected mostly from herpangina patients, the virus became increasingly detected from HFMD patients since 2009 (IASR 33: 55-56, 2012), becoming the dominant strain isolated from HFMD patients in large epidemic years during 2011-2017 (Fig. 5 in p. 193) (see pp. 193, 195, 196 & 197 of this issue). HFMD due to CV-A6 has been characterized by atypical manifestations, such as frequently high fever (≥38°C), extensive blisters in the femoral and gluteal regions and onychomadesis (see p. 198 of this issue). In recent years, atypical HFMD caused by CV-A6 has spread globally, including in Asia.

EV-A71 infection spread among infants in Malaysia, Taiwan, China, Vietnam, Cambodia and other countries in eastern Asia since the late 1990s; it caused complication of central nervous system (CNS) (such as encephalitis, brain stem encephalitis, and paralysis) with severe and often fatal outcomes (see p. 201 of this issue). Fatality has been high when the patients developed neurogenic pulmonary edema or cardiopulmonary failure. From 2008 to 2012, China reported about 7,200,000 HFMD cases; among them, 82,484 were severe and 2,457 were fatal (Lancet Infect Dis 14: 308-318, 2014). Most patients were under 5 years of age, and the fatality was highest among those aged 12-23 months. Ninety percent of the fatal cases were EV-A71 positive. In Japan, severe or fatal HFMD cases have been rare. However, sporadic occurrences have been reported, and during HFMD epidemics associated with EV-A71, CNS complications increased among infants. While CV-A6 is known to cause less CNS complications, as CV-A6 has also been isolated from encephalitis cases (see p. 195 of this issue), the association between CNS complications and enteroviruses other than EV-A71 warrant further investigation (IASR 37: 33-35, 2016).

Prevention and other measures: For both HFMD and herpangina, viral transmission is primarily through droplet or contact. Handwashing and appropriate disposal of body waste is therefore important for preventing spread of infection. Treatment for enterovirus infection is, as a rule, symptomatic. Notably, Asian countries that have experienced large scale epidemics involving cases of severe enterovirus infections have been developing vaccines for preventing disease and severe outcomes. In 2016, China introduced to the market the world’s first inactivated EV-A71 vaccine (see p. 203 of this issue).

Concluding remarks: For patients suspected of CNS complications due to enterovirus infection, cerebrospinal fluid is suitable for laboratory diagnosis. However, compared to Enterovirus B which are important causes of aseptic meningitis, Enterovirus A have a lower detection rate from cerebrospinal fluid. Therefore, when infection of Enterovirus A is suspected, testing other samples such as throat swabs and fecal specimens is recommended. Continued laboratory surveillance of enteroviruses and feedback of such information are important.

Copyright 1998 National Institute of Infectious Diseases, Japan

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