Japan. J. Med. Sci. Biol., 26, 143-147, 1973

REPORTS

EPIDEMIC OF HAND, FOOT AND MOUTH DISEASE IN

From the middle of the year 1969, increased isolation of coxsackievirus group A type 16 (CA16) from cases of hand, foot and mouth disease (HFMD) was reported to the WHO Regional Reference Centre for Enteroviruses, . In 1970 the disease appeared to have been spread over the whole country. Since HFMD is not officially reported to the Ministry of Health and Welfare, the Reference Centre was interested to gather information on the general aspect of the epidemic. So inquiries for infor- mation were sent to the collaborating laboratories reporting monthly enterovirus isola- tion to the WHO through the Reference Centre, as well as to other laboratories and medical colleges, where laboratory diagnoses of viral diseases are made. Information was also obtained from pediatricians and dermatologists in medical colleges and other large hospitals, since the clinical picture of the disease is characteristic. Sixty-four institutions in 42 of the 46 prefectures collaborated in this investiga- tion. In 7 of the 42 prefectures, outbreaks of the disease were confirmed, but no special investigation was carried out. In other areas more detailed investigations including virus isolation and/or serological survey have been carried out. This epidemic of HFMD appears to be the first large-scale one in Japan since the first description of the disease (Robinson, Doane and Rhodes, 1958). Although some publi- cations reporting local outbreaks during the epidemic have appeared, it seems justified to record the whole aspect of the epidemic based on the information collected by the Reference Centre. This report deals with analyses of the information collected including the publications on the past small outbreaks. The first clinical description of the disease in Japan was made by Nakamura et al. (1965) on two cases observed in Tokyo in 1963, but the attempt to isolate the etiological agent was unsuccessful. The second report of the disease (Watanabe and Uryu, 1967) described 19 clinically diagnosed cases occurring in in 1966, but no virological investigation was carried out. The first isolation of CA16 virus from clinical specimens of HFMD in Japan was reported in 1967 from (Sawada, Nakamura and Ito, 1968), (Ichikawa, 1969; Yoshida, Kubota and Noguchi, 1970), (Takayasu and Kawazu, 1969) and Hyogo (Shinkai, Maeda and Sano, 1968). Nineteen of 85 cases examined virologically were confirmed to have been due to CA16 virus infection. Enterovirus survey among healthy children carried out since 1962 by the Department of Enteroviruses, National Institute of Health, Tokyo, recorded the first isolation of CA16 virus from the stool of a healthy child in April 1964, fol- lowed by 2 isolations each in 1966, 1967, and again one isolation in 1968 (Komatsu, Mukoyama and Kohara, to be published). In 1967, outbreaks of HFMD due to CA16 virus were reported from the central part of the main island. In 1968, another outbreak was reported from Kyushu, the south-western island (Shingu and Shingu, 1969; Shingu et al., 1970; Matsumoto et al., 1971); in 1969, several other outbreaks

143 144 REPORTS Vol. 26

occurred in the central as well as in the northern parts of the mainland. Thus it appeared that from 1967 to 1969, CA16 virus was disseminated over the whole country, providing foci of the virus for the epidemics of HFMD in 1970 (Mori, Kitahara and Takamori, 1971; Hidano et al., 1971; Saito et al ., 1972). In 1969, 176 cases were examined virologically and 100 of them were proved to have been due to CA16 virus infection; in 1970, 1,277 cases were examined and 617 of them were shown to have been due to CA16 virus infection. Thus, most outbreaks of HFMD occurring in 1969 and 1970 in the whole country were due to CA16 virus infection (Table I) (Fig. 1). Several other serotypes of enteric virus were isolated from clinical specimens (feces and throat swabs) of HFMD patients; in 1967 one each of CA 4

TABLE I Incidence of hand, foot and mouth disease in Japan

Region I : Hokkaido II: Tohoku III : Kanto IV: Chubu V : Kinki VI: Chugoku VII: Shikoku VIII: Kyushu and 9, and echo 6 ; in 1968 one each of CA 4, CA 6, and CA 10, and two of CA 8 ; in 1969 one each of CA 5 and CA8 and two of CA 10; in 1970 one each of CA 6 and CB 5 and two each of CA 10 and adeno 2 and 14 of CA 5. In 1971 a few clinical cases were reported, but none was confirmed virologically to have been due to CA16 virus. 145 1973 REPORTS

Fig. 1. Map of Japan.

Fig. 2. Age distribution of HFMD clinically diagnosed (1970). 146 REPORTS Vol. 26

Age distribution of a portion of HFMD cases including those virologically con- firmed in 1970 are shown in Fig. 2. The other cases occurring in 1970 as well as those occurring from 1967 to 1969 showed essentially the same age distribution. It is noticed that the highest frequency was obtained with the age group of one year, 32.6 % of those reported, and that more than 80% of total cases were in the age group under 4 years. Cases were, however, widely distributed also in the older age groups, though far less frequently. Sero-suveys on the age distribution of neutraliz- ing antibodies against CA16 virus were carried out in several labolatories including this laboratory with the serum specimens collected before the present epidemics. The results showed that the antibody was positive in the age groups above 3 to 4 years, indicating that this virus had been prevalent before the present epidemic. Clinical pictures of HFMD were generally very mild and many cases may have recovered themselves without visiting physicians. The actual cases occurring in 1970, therefore, should have been much more than we estimated from the information obtained. In epidemiology and etiology of HFMD, there are some problems to be solved. Retrospective sera-surveys for the neutralizing antibody against CA16 virus in serum specimens collected before the first isolation of the serotype in this country (1964) will clarify whether CA16 virus had been indigenous or was imported, later. It was indicated that it took several years for CA16 virus to be disseminated throughout the whole country, resulting in the epidemic of 1970. Whether or not the virus changed in pathogenicity during this period will be answered by further studies. Suto et al. (1971) and Numazaki et al. (1971) who isolated CA16 virus in Vero cell cultures reported that virus strains isolated from vesicles were more difficult to be neutralized with the type-specific antiserum than those isolated from throat swabs or stools. This finding together with the observations that considerably potent neutraliz- ing antibody or CF antibody or both were detected in patient's sera when the virus was isolated from vesicle fluids may throw light on pathogenesis of this virus in developing skin and mucous vesiculation.

ACKNOWLEDGEMENT

We greatly appreciate the collaboration of the doctors who made their data available.

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SUTO, T. AND MORITA, M. (1973): Hand, foot and mouth disease. Nihon-Rinsho, 29,

1137-1142 (text in Japanese). TAKAYASU, S. AND KAWAZU, T. (1969): Hand, foot and mouth disease in City,

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nese).

Department of Enteroviruses, ISAMU TAGAYA (WHO Regional Reference Centre for Enteroviruses), YASUO MORITSUGU National Institute of Health, Musashimurayama, Tokyo 190-12, Japan

(Received : March 5, 1973)

多 ケ谷 勇 ・森 次 保 雄(国 立 予 防 衛 生 研 究 所腸 内 ウイ ル ス 部 武 蔵村 山市 中 藤3260)