国立感染症研究所

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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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