The Topic of This Month Vol.27 No.12(No.322)

Diphtheria as of 2006 Japan

(IASR 27: 331-332; December, 2006)

Diphtheria is a membranous disease of the upper respiratory tract caused by infection with Corynebacterium diphtheriae , sometimes involving blepharoconjunctiva, auris media, genitalia and skin. If such systemic symptoms as coma or myocarditis occur by the toxin produced by the organisms infected and multiplied, peril of death will become more likely. The case-fatality rate in developed countries is estimated at 5-10%.

In Japan, diphtheria is defined as a category II infectious disease in compliance with the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (Infectious Diseases Control Law) enacted in April 1999 and physicians who have diagnosed diphtheria are obliged to notify all cases (for the case definition for notification, refer to

Thus far within the country, epidemics once occurred after the World War II, nevertheless diphtheria has been on the marked decrease owing to the wide use of vaccination and recently it only seldom occurs. In the former Soviet Union, approximately 160,000 people were infected and developed symptoms and approximately 5,000 of them died during 1990-1998 (see p. 335 of this issue). From this episode, experts realized the importance of surveillance and vaccination for diphtheria again, and the European Laboratory Working Group on Diphtheria concerning epidemiology, diagnosis, treatment and prevention of diphtheria has been established in Europe (see p. 336 of this issue). Although the main etiological agent of diphtheria is diphtheria toxin, there have recently been a number of reports on isolation of nontoxigenic organisms from diphtheria cases in UK, and also from a case of septicemia was reported in Japan in January 2006. A closely related species, Corynebacterium ulcerans , produces diphtheria toxin, causing diphtheria-like symptoms, has been isolated in Europe and Japan and paid attention (see p. 333-335 and p.336-337 of this issue).

In Japan, the immune status of people against diphtheria is being monitored by the National Epidemiological Surveillance of Vaccine-Preventable Diseases (NESVPD). In this survey, approximately 10 nationwide prefectural and municipal public health institutes (PHIs) conduct surveillance for diphtheria toxin-neutralizing antibody (antitoxin) in serum samples from healthy children and adults (all age groups were covered for the first time in 2003). Approximately 1,000-1,500 specimens were surveyed once every 4-5 years and the National Institute of Infectious Diseases (NIID) summarizes the nation-wide data. Through this surveillance, as shown below, it has been confirmed that diphtheria antibody-positive rate among children in Japan has been kept very high owing to vaccination and this has been considered to be the largest factor suppressing occurrence of diphtheria.

Incidence of diphtheria and history of vaccination: Notified cases of diphtheria in Japan (notification in compliance with the Communicable Diseases Prevention Law until March 1999) reached approximately 86,000 in 1945 (approximately 1/10 of them died) and markedly decreased afterwards (Fig. 1). After enforcement of the Infectious Diseases Control Law, one death case was notified from Gifu Prefecture in 1999 (IASR 20: 302-303, 1999). Another suspected case was notified from Hiroshima Prefecture in 1999 and also from Tochigi Prefecture in 2000. They are not counted; as suspected cases of diphtheria are not liable to notification.

In Japan, monovalent diphtheria vaccine (D) was adopted in 1948 for routine vaccination, followed by diphtheria-pertussis combined vaccine (DP) in 1958 and DTP supplemented with adsorbed tetanus toxoid (T) in 1968. Due to the postvaccination fatal accidents occurring in 1975 after DTP injection, routine DTP vaccination was interrupted for three months. In 1981, an adsorbed diphtheria-tetanus-acellular pertussis (DTaP) combined vaccine (purified Bordetella pertussis protein antigens replaced killed B. pertussis whole cells) was introduced. In April 1995, the amendment of the Preventive Vaccination Law came into effect, and the following standard vaccination schedule was proposed (when tetanus was formally adopted for routine vaccination). For a primary vaccination series, three doses of DTaP are to be given at 3 to 8-week intervals to infants of the age between 3 and 12 months and a booster injection 12 to 18 months after the primary series. For an additional booster, adsorbed diphtheria and tetanus toxoid (DT) is to be injected once at the age of 11 to 12 years.

Diphtheria antibody (antitoxin) prevalence by NESVPD in 2003: In the latest surveillance in 2003, 1,447 serum samples were collected from all age groups in eight prefectures (Yamagata, Ibaraki, Tokyo, Fukui, Osaka, Ehime, Fukuoka, and Miyazaki Prefectures). The antibody prevalence rate was on the increase from 0 to 3 years of age owing to vaccination (Fig. 3). About 80 % of 1-4 year children possessed an antibody level higher than 0.1 IU/ml, which is regarded as the minimum protective level against symptomatic diphtheria (Hasselhorn, H. M., et al ., Vaccine 16 (1): 70-75, 1998) (Fig. 2). After that toward 40-44 years of age, the rate decreased gradually reiterating increase and decrease. A drop was seen at 25-29 years of age, which reflects the temporary interruption of vaccination in 1975 and the low vaccine coverage period until introduction of DTaP vaccine in 1981. A sudden drop to below 10% was seen at 45-49 years of age, however, at ages elder than these, the rate increased again to about 20%, but not to the level of young people. Concerning the antibody prevalence rate by year (Fig. 3), the rate of 0-4 years of age was on the increase. The antibody prevalence rate above 0.1 IU/ml peaked at 3-4 years of age, which gradually decreased, keeping higher than 50% up to 15 years of age. By vaccination history (Fig. 4), those who completed basic immunity (4-dose primary series and a booster) possessed a high antibody prevalence rate, while those receiving only the first dose of the primary schedule insufficiently low rate, being 35%.

In the 2003 survey, all those having diphtheria vaccination history (2,402 cases including other objects of survey than those of diphtheria), the rate of vaccinated (once or more) was high, being higher than 90%, but the vaccination rate of 4 times or more of 3-9 years of age was insufficient, being 60-70%.

Clinical and laboratory diagnosis: Since no more diphtheria cases can be seen within the country, we are anxious about falling off of physicians who can diagnose diphtheria and of laboratory workers who have learned isolation and identification of C. diphtheriae . To prepare for emergencies of occurrence of diphtheria, the NIID and PHIs, with cooperation of clinical doctors, will make a manual for clinical diagnosis, etiological diagnosis, and therapy ( to maintain techniques. For laboratory methods, also refer to

Advice for vaccination: Although diphtheria cases occurring in the former Soviet Union accounted for approximately 90% of all diphtheria cases occurring in the whole world during 1992-1996 [Emerging Infectious Diseases 4(4): 539-550, 1998], epidemics turned to end owing to intensification of vaccination from 1995. However, in many countries in the world, mainly in developing countries and particularly in Belarus, Georgia, Latvia, Russian Federation, and Ukraine, it has been reported that the situation calls for attention even now (see p. 335 of this issue). Even adults, depending upon the travel destination, voluntary immunization before departure is desirable (if basal immunity against diphtheria is present, one booster injection, if there is no basal immunity, at least twice or more injections). For booster injection, DT or adsorbed diphtheria toxoid for adult is being used. For children, it is important to bestow basic immunity by routine immunization.

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