国立感染症研究所

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 The Topic of This Month Vol. 33, No. 5 (No. 387)


 Enterohemorrhagic Escherichia coli infection in Japan as of April 2012
(IASR 33: 115-116, May 2012)

Enterohemorrhagic Escherichia coli (EHEC) infection is a category III notifiable infectious disease in the National Epidemiological Surveillance of Infectious Diseases (NESID) under the Infectious Diseases Control Law.  Immediate notification after the diagnosis is mandatory requirements for physicians (http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-03-03.html).  When an EHEC infection is notified as food poisoning by physicians or judged as such by the director of the health center, the local government investigates the incident and submits the report to the Ministry of Health, Labour and Welfare (MHLW) in compliance with the Food Sanitation Law.

Prefectural and municipal public health institutes (PHIs) conduct isolation of EHEC, serotyping and VT typing, and report the results to Infectious Disease Surveillance Center (IDSC).  Department of Bacteriology I, National Institute of Infectious Diseases (NIID), conducts molecular epidemiological analysis, whose result is made available through the PulseNet Japan (see p. 127 of this issue).

In year 2011, there was a large O111 outbreak in Toyama and other prefectures which accompanied hemolytic uremic syndrome (HUS) and encephalopathy (see pp. 118 & 119 of this issue).

Cases notified under NESID: In 2011, total 3,938 EHEC infection cases, 2,660 symptomatic patients and 1,278 asymptomatic carriers, were reported (Table 1).  As in previous years, there was a large incidence peak in summer (Fig. 1).  Incidence (cases per 100,000 population) was highest in Yamagata (26.53), Toyama (17.74) and Shimane (10.67) Prefectures, which all experienced large outbreaks (Fig. 2, left panel and Table 2).  As in previous years, incidence of EHEC was highest among the age group of 0-4 years followed by that of 5-9 years (Fig. 3).  Among prefectures, EHEC incidence (cases/100,000) in population under 4 years of age was highest in Iwate, Yamagata and Shimane Prefectures (Fig. 2, right).  Symptomatic cases were, as in previous years, less frequent among people in their 30's, 40's and 50's and more frequent among younger (below 20 years) and older (above 65 years) groups (Fig. 3).  There were 102 HUS cases (including serodiagnosed cases, see p. 130 of this issue), which corresponded 3.8% of the symptomatic cases (see p. 128 of this issue).  Among 61 EHEC-positive HUS cases, 6 cases were isolation positive for both O157 and O111, 42 cases for O157, 9 cases for O111, two cases for O26, and one case each for O121 and for O145; all cases were positive for VT2 with or without VT1.  Seventeen cases were fatal, among whom 11 had HUS.  The number of deaths reported in 2011 was the highest since the NESID started in 1999.

Reports of EHEC from PHIs: In 2011, PHIs reported to IDSC 2,213 EHEC isolates, far less than the reported number of EHEC infection cases (Table 1).  The discrepancy is due to the situation where only a small proportion of isolates in hospitals or commercial laboratories are sent to PHIs.  The most frequent O-serogroups were O157 (59%), O26 (21%) and O145 (5.7%) (see Table on p. 117).  As for types of VTs, VT1-VT2 double positives were 78% of O157 isolates (53-70% in 1997-2010).  Among O26, 79% were VT1 single positives.  Among O145, 50% were VT1 single positives and 47% VT2 single positives.  Frequency of HUS and encephalopathy among O111 cases was exceptionally high (see Table on p. 117) due to the large outbreak as stated below.

Outbreaks: In 2011, PHIs reported to IDSC 29 EHEC outbreaks, including 15 outbreaks caused by O157.  Among 18 outbreaks involving ten or more EHEC-positive cases (Table 2), 13 outbreaks were suspected to be food/water-borne infections, and five person-to-person transmission.  In 2011, 25 EHEC incidents involving 714 patients (including bacteria-negative cases) were reported by prefectures in compliance with the Food Sanitation Law (27 incidents and 358 patients in 2010) (http://www.mhlw.go.jp/topics/syokuchu/04.html).

In 2011, there was a large EHEC O111 outbreak involving yakiniku chain restaurants due to consumption of yukhoe (Korean dish of raw beef and egg yolk) (see pp. 118 & 119 of this issue).  Among 181 patients, O111 was isolated from 85 patients (median age 20 years), among whom 34 patients developed HUS, 21 patients further developed encephalopathy and five died.  HUS cases were more frequent (16 cases) among adult female above 16 years of age.  O111:H8 (VT2 positive) was isolated from the conserved part of the original meet preparations distributed to the chain restaurants.

Prevention and countermeasures: For prevention of EHEC infections, adherence to the principles of food poisoning prevention and avoidance of consumption of raw or under cooked meet are important (http://www.mhlw.go.jp/topics/syokuchu/index.html).  In response to successive food poisoning incidents due to consumption of raw beef meet, MHLW revised the standard of food meet consumable raw (IASR 32: 168-169, 2011 and see p.132 of this issue), and issued the public notice number 321 in October 2011(http://www.mhlw.go.jp/stf/kinkyu/2r9852000001bbdz.html).  In addition, MHLW has considered additional regulation of beef liver consumable raw.  As EHEC O157 are often found deep inside of the liver, MHLW considered prohibition of raw beef liver consumption and already initiated necessary procedures (notice 0409 number 3 issued by Department of Food Safety, MHLW, on April 9, 2012, http://www.mhlw.go.jp/topics/syokuchu/dl/120409_01.pdf).

Similarly as Shigella, EHEC establishes infection even at minute doses and can spread from person to person rather easily.  In 2011, there were not a few EHEC outbreaks in nursery schools (Table 2).  For preventing outbreaks, appropriate hygienic practice, such as routine hand washing and sanitary use of children's padding pools, should be observed.  The health center should provide the patients' family members with thorough instructions necessary for preventing the secondary infections.

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 The Topic of This Month Vol. 33, No. 4 (No. 386)


 Buruli Ulcer in Japan and in the World 2012
(IASR 33: 85-86, April 2012)

Buruli ulcer is caused by Mycobacterium ulcerans and its subspecies, M. ulcerans subsp. shinshuense .  The main clinical manifestation is skin ulcer, but when diagnosed at early stage, it may present with pre-ulcer symptoms including erythema, nodule, or edema (Table 1).  The disease was so named after Buruli County in Uganda, where many cases of “large skin ulcers” were found.

Buruli ulcer and World Health Organization (WHO): WHO has classified Buruli ulcer as one of the neglected tropical diseases (NTD) (URL: http://www.who.int/buruli/en/).  It started the Global Buruli Ulcer Initiative in 1998 to promote its diagnosis, therapy, prevention and basic research.  Leprosy Research Center, National Institute of Infectious Diseases, Japan, serves as the center of activities on Buruli ulcer in Japan.

Epidemiology of Buruli ulcer: Up to now, more than thirty countries in the world have reported Buruli ulcer cases to WHO, which receives about 5,000 reports of new cases annually.  The reported numbers are probably underestimates (see p. 87 of this issue).  It is most frequent in the West to Central African countries; te d’Ivoire, Ghana and Benin are reporting 2,500, 1,000 and 500 cases a year, respectively.  Many of the patients in African region are under 15 years of age (see p. 88 of this issue).  The patients have been reported from Australia and Mexico, too.

Among the South-East Asian countries, only Japan has reported cases of Buruli ulcer till now, except for one case diagnosed in Europe that acquired the infection in China.  In Japan, Buruli ulcer was first reported in 1980 (published in 1982); and since 2004 onwards, it is reported every year owing to its recognition among clinicians through academic meetings and publications (Fig. 1 & Fig. 2).  Up to the end of 2011, total 32 cases, all acquired infection inside Japan, have been reported.

The reason for the relatively small number of reports of Buruli ulcer from developed countries including Japan is partly due to the low awareness among the people.  Moreover, many cases are cured in the early stages before the development of ulcers by antimicrobial agents that are effective to the causative bacteria.

Properties of causative agents and infection routes: The habitats of both M. ulcerans and M. ulcerans subsp. shinshuense are soil, water and other environment.  The optimum growth temperature is 30-33°C, but it can grow at room temperature (25°C) (Table 2).  All the foreign isolates have been M. ulcerans .  All the isolates from Japanese patients including the one isolated from the patient infected in China were M. ulcerans subsp. shinshuense .

The bacteria produce mycolactone, a toxic lipid, which is cytotoxic and immune suppressive (see p. 89 of this issue).  It causes cellular necrosis, which is responsible of skin ulcers.  As the toxin damages peripheral nerve Schwann cells, the developed ulcers are almost painless.

The infection route of Buruli ulcer is unknown.  Epidemiological studies have shown that the disease is frequent among people, particularly children, living near rivers, ponds and wetlands (see p. 90 of this issue).  Therefore, it is considered that the causative bacteria residing in soil or water penetrate the skin directly or through skin injury or by vector's bite.  Presence of carrier and/or vector animals were suspected, which needs to be confirmed through further investigations.  No person-to-person infection cases have been reported.

Clinical pictures of Buruli ulcer: The frequently affected sites are exposed areas of the skin, such as, on the upper and lower extremities and occasionally on the face.  It starts with a symptom of mosquito bite-like red spot or red papule, which gradually progresses to a painless subcutaneous nodule, then to plaque and edema.  In several days or weeks, the center of the lesion ulcerates and develops into an ulcer (see p. 91 of this issue), which is almost painless unless there is secondary infection.  If the diagnosis and therapy is delayed, the ulcer becomes larger, and arthrogryposis and scar may remain even after the cure.  Fever is rare and the patients' condition is generally unimpaired.  Buruli ulcer seldom becomes fatal.

Laboratory diagnosis: It consists of microscopic examination of acid-fast stained swab specimens obtained from the center or the edges of ulcers which are streaked on a slide glass (smear test).  Other methods include acid-fast bacterial culture of skin or pus specimens, PCR detection of the specific DNA [insertion sequence (IS) 2404 ] from swab of the ulcer lesion, pus or biopsy specimens (see p. 93 of this issue), and pathological examination of the tissue specimens for the presence of acid-fast bacteria.

Once the bacterial culture is successful, the identification of bacteria is done by DNA-DNA hybridization (DDH Mycobacteria 'Kyokuto').  With this method, as M. ulcerans and M. ulcerans subsp. shinshuense are genetically close to M. marinum , any specimen positive for M. marinum should be checked by PCR for final diagnosis.

Definitive diagnosis should be based on detection of bacteria, as Buruli ulcer is an infectious disease.  As the isolation of bacteria requires several weeks to months, the diagnosis criteria used in Japan are as follows: 1) ulcerative skin lesion (with or without pain), 2) necrotic pathological changes in skin histology, and 3) positive PCR results (detection of the causative bacteria specific IS2404 ).  In developing countries, the diagnosis has been based mainly on clinical symptoms, but in recent years, more laboratories started to have equipments needed for the PCR diagnosis with assistance of WHO.

Clinically similar diseases include cutaneous tuberculosis, leprosy, cutaneous leishmaniasis, skin parasitization of fly larvae, diabetic ulcer, bedsore, pyoderma gangrenosum, necrotizing fasciitis, necrobiosis lipoidica, malignant tumor, ischemic skin lesion, and wound lesion.  Differential diagnosis by dermatologists is required.

Therapy and cure of Buruli ulcer: Therapy consists of combined administration of two or three of the following antibiotics; rifampicin (RFP), streptomycin (SM), amikacin (AMK), clarithromycin (CAM), and quinolone.  WHO recommends daily administration of RFP and SM for eight weeks.  However, SM-RFP combination therapy for 4 weeks followed by a 4-week treatment with RFP and CAM is conducted occasionally on account of inconvenience of requiring injection for SM administration.  In Japan, oral administration of RFP, CAM and quinolone is quite frequent, which has been reported clinically effective.  Large ulcers need surgical intervention including skin grafting.

As the infection source is not identified yet, there are no effective preventive measures.  As Buruli ulcer is very rare in Japan and the epidemic feature is obscure, early diagnosis is the most important.

Challenges in future: Though it has been regarded as tropics-specific disease, Buruli ulcer is also found in warm-temperature regions like Japan and Australia.  The number of patients in Japan is increasing in the recent years, but they can be cured if diagnosed early and treated immediately.

Elucidating mode of infection, particularly infection source and potential vectors, is necessary for prevention.  Early detection of the patients should be promoted in Japan, and one key measure is to raise awareness among clinicians.  Since there are no definite report of Buruli ulcer patients from other Asian countries, our experience should be shared with these countries for detection of Buruli ulcer patients that may possibly existing in these countries.

Copyright 1998 National Institute of Infectious Diseases, Japan

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