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Case Report/Case Series |

Buruli Ulcer Caused by Mycobacterium ulcerans Subsp shinshuense A Rare Case of Familial Concurrent Occurrence and Detection of Insertion Sequence 2404 in Japan FREE

Mikio Ohtsuka, MD1; Nobuyuki Kikuchi, MD1; Toshiyuki Yamamoto, MD1; Tatsuo Suzutani, MD2; Kazue Nakanaga, PhD3; Koichi Suzuki, PhD3; Norihisa Ishii, MD3
[+] Author Affiliations
1Department of Dermatology, Fukushima Medical University School of Medicine, Fukushima, Japan
2Department of Microbiology, Fukushima Medical University School of Medicine, Fukushima, Japan
3Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, Japan
JAMA Dermatol. 2014;150(1):64-67. doi:10.1001/jamadermatol.2013.6816.
Text Size: A A A
Published online

ABSTRACT

Importance  Buruli ulcer, a severe skin infectious disease caused by Mycobacterium ulcerans, is prevalent in tropical and subtropical areas. Recently, cases of Buruli ulcer have been increasing in Japan. All cases have been sporadic, and to date the pathogenic organism has not been detected in materials from the environment.

Observations  Three members of the same family were seen with large indurated plaques on their face and extremities in the winter of 2010. Skin biopsy specimens of their lesions showed extensive necrosis of deep dermis and subcutaneous fat. Acid-fast bacilli were detected in each biopsy specimen by Ziehl-Neelsen stain, and bacteriological analysis of cultured microorganisms revealed the strains to be M ulcerans subsp shinshuense. The patients were treated with a combination of antibiotics and surgical debridement. Insertion sequence 2404 was detected from a crayfish captured in a stagnant water channel in the backyard of the family’s house.

Conclusions and Relevance  We report a rare instance of familial occurrence of Buruli ulcer in Japan. Detection of insertion sequence 2404 from a crayfish suggests that the pathogenic organism may reside in an aquatic environment in Japan, as in other endemic areas. To prevent this serious infectious disease, further investigation is needed to clarify the transmission pathway.

Figures in this Article

Buruli ulcer (BU) is a severe skin infectious disease caused by Mycobacterium ulcerans. It usually manifests as an indurated plaque that develops extensive necrosis of the affected skin. Mycobacterium ulcerans is considered an environmental pathogen, residing in an aquatic locale, and is thought to be transmitted by direct contact with contaminated water through minor trauma or by uncertain aquatic vectors that bite humans.1 Buruli ulcer most frequently occurs in tropical and subtropical areas, especially in West African countries such as Uganda, Ghana, and Benin.1 Other known endemic areas are located in Australia, Southeast Asia, China, Central America, and South America.1,2 According to a study by the World Health Organization,3 more than 5000 cases are reported annually from more than 30 countries; however, many unreported cases of BU are presumed to exist.

In 1982, Mikoshiba et al4 described a Japanese patient seen with an ulcerative lesion simulating BU. The isolated Mycobacterium from the lesion had bacteriological characteristics similar to those of M ulcerans, and the strain was later named M ulcerans subsp shinshuense based on the homology of the 16S ribosomal RNA (rRNA) gene sequence and the presence of insertion sequence 2404 (IS2404), which are specific to M ulcerans and related species.1,5 Since that first report, more than 30 Japanese patients diagnosed as having BU have been described in the literature.6 We report herein additional cases of BU that concurrently occurred in a Japanese family.

REPORT OF CASES

Case 1

In December 2010, a 2-year-old Japanese girl from the Aizu region of the Fukushima prefecture presented with asymptomatic swelling of her right cheek. One month earlier, her family had first noticed the eruption, which had gradually enlarged. At first examination, an indurated plaque, 5 cm in diameter, with a central ulcer was observed on the right cheek (Figure 1A). The patient was afebrile and otherwise healthy. She was treated with oral cefcapene pivoxil for 1 week, without benefit. Based on a presumed diagnosis of nontuberculous mycobacterial infection or neoplastic disease, a skin biopsy specimen was obtained from the right cheek. A hematoxylin-eosin–stained section showed extensive necrosis of deep dermis and subcutaneous fat (Figure 1B). Coagulation of dermal vessels was also seen. Inflammatory cells, such as neutrophils and lymphoid cells, were scarce, and no granulomatous aggregate of histiocytes, epithelioid cells, or multinucleated giant cells was observed. Ziehl-Neelsen stain initially revealed no acid-fast bacilli. Polymerase chain reaction (PCR) targeting Mycobacterium avium-intracellulare complex was negative. Bacterial culture using a tissue sample was also negative for microorganisms, including Mycobacterium species. In late December 2010, an indurated plaque with a small ulcer appeared on her left leg (Figure 1C). A biopsy specimen from the leg lesion demonstrated numerous acid-fast bacilli by Ziehl-Neelsen stain (Figure 1D).

Place holder to copy figure label and caption
Figure 1.
Clinical and Histological Features of Case 1

A, A red indurated lesion with a central ulcer on the right cheek. B, The skin biopsy specimen of a facial lesion showing extensive necrosis of deep dermis and subcutaneous fat. Inflammatory infiltrates are observed only scarcely (hematoxylin-eosin, original magnification ×100). C, A slightly red indurated plaque with a small central ulcer on the left leg. D, Numerous acid-fast bacilli detected by Ziehl-Neelsen stain of the biopsy specimen of a leg lesion (original magnification ×400).

Graphic Jump Location
Case 2

The 5-year-old brother of patient 1 subsequently was seen because of an asymptomatic indurated eruption had appeared on the right forearm 3 weeks earlier, and the center of the lesion had gradually ulcerated. At first examination, a large plaque, 6 cm in diameter, was seen on the ulnar aspect of the right forearm (Figure 2A). His medical history was unremarkable. A skin biopsy specimen revealed the same histological findings as had been observed in patient 1. Acid-fast bacilli were detected in a smear and formalin-fixed section by Ziehl-Neelsen stain.

Place holder to copy figure label and caption
Figure 2.
Clinical Features of Case 2 and Case 3

A, A slightly red indurated plaque with a small necrotic ulcer on the right arm of case 2. B, A red indurated plaque with central concavity on the right wrist of case 3.

Graphic Jump Location
Case 3

A month later, the previously healthy 37-year-old mother of patients 1 and 2 was seen to discuss her childrens’ conditions, she was noted to have an indurated red plaque, 4 cm in diameter, on her right wrist (Figure 2B). She had noticed the eruption around the time her children’s condition was noticed, which had gradually enlarged, without any subjective symptoms. A biopsy specimen revealed the same findings as had been observed in patients 1 and 2.

Clinical Course and Treatment

All 3 patients were referred for further investigation and treatment of their disease. According to a tentative diagnosis of BU based on the histological findings and detection of acid-fast bacilli from skin samples, the patients were treated with oral administration of levofloxacin (12 mg/kg), clarithromycin (16 mg/kg), and rifampicin (10 mg/kg). The necrotic tissue of their lesions on the extremities was surgically removed and covered by a skin graft. The facial lesion in patient 1 gradually healed without surgical treatment. Oral antimycobacterial drugs were discontinued 9 months after treatment began. At 27 months’ follow-up, their lesions had not recurred.

Bacterial Culture and Identification of Pathogenic Organisms

Skin biopsy samples obtained from the patients were inoculated on 2% Ogawa medium and incubated at 27°C. After 41 to 58 days of culture, small yellow-white colonies were obtained from each sample. The sequence of the 16S rRNA gene in the isolated strains from our patients was identical to that of M ulcerans subsp shinshuense American Type Culture Collection 33728 but differed from that of M ulcerans Agy99 at positions 492, 1288, and 1449-1451, which are known to be useful for differentiating M ulcerans subsp shinshuense from M ulcerans and Mycobacterium marinum (Table).7 Insertion sequence 2404 was detected from the strains by PCR. In addition, our strains lacked 1 of 8 genes encoding mycolactone on the virulence plasmid pMUM001 by PCR.7 Based on these findings, all strains obtained from our patients were determined to be M ulcerans subsp shinshuense.

Table Graphic Jump LocationTable.  16S Ribosomal RNA Gene Sequences Differentiating Mycobacterium ulcerans and Related Species
Detection of Pathogenic Organism From the Environment Near the Residence of the Cases

The family lives in a house surrounded by rice fields in a rural town. A stagnant agricultural water channel exists in the backyard, where the 2 children usually play. After obtaining informed consent from the family, we collected water samples at 2 different sites of the channel and 2 crayfish. Detection of the pathogenic strain was performed using a highly sensitive method capable of detecting small amounts of DNA as described previously.7,8 Briefly, DNA extracts from concentrated water and homogenized crayfish were subjected to whole-genome amplification PCR,8 and the amplified DNA was subsequently analyzed by PCR using primers targeting IS2404.7 The expected 278–base pair (bp) product corresponding to IS2404 was detected from one of the crayfish, and the sequence of the 278-bp product was identical to that of IS2404 of M ulcerans.

DISCUSSION

Buruli ulcer initially manifests as a small red papule or subcutaneous nodule that gradually extends to the periphery. A lesion develops with a large ulcerative plaque covered by necrotic tissue, resulting in scarring, contracture, and disability. Despite its large size, BU is usually painless,9 which often leads to delay in seeking medical care until the lesion reaches an advanced stage. Cytotoxic and immunosuppressive properties of mycolactone produced by M ulcerans are considered to have a major role in the pathogenesis of BU.9 Coagulation of blood vessels, which is frequently observed in the skin lesions, may also account for extensive necrosis of the affected skin.1,9

In 2011, Nakanaga et al10 reviewed clinical, geographic, and bacteriological features of 19 Japanese patients diagnosed as having BU. All cases were sporadic, with the age of patients ranging from 8 to 81 years. The cases were distributed across various areas of Honshu, the main island of Japan; no endemic focus was observed. Most patients first noticed their lesions during the autumn or winter. In contrast to the endemic areas in which BU is caused by M ulcerans, all isolated organisms from Japanese patients were determined to be M ulcerans subsp shinshuense by sequencing of the 16S rRNA gene. Despite the difference in the pathogenic strains, clinical features are similar between the Japanese patients and those from the endemic areas except for the occasional report of a painful lesion, which is more frequent among Japanese.6 Buruli ulcer is known to occur mainly in regions near wetlands, such as ponds, swamps, and slow-flowing or stagnated water; however, no Japanese patients have been reported to have direct evidence of contact with an aquatic environment before the onset of their skin lesion.10

We report herein a rare instance of familial occurrence of BU in Japan, in which 3 family members developed BU. Direct transmission of the pathogenic organism among the family during their daily life seems unlikely because their lesions appeared almost simultaneously. In the endemic areas, a family history of BU is observed in 12% to 23% of patients manifesting the lesions.1114 Similar routines and a common environmental exposure may increase the risk of familial occurrence of BU.11,12 However, case-control studies have demonstrated conflicting results about the familial relationship of BU: some investigators concluded that there was no significant difference in the family history of BU between cases and controls,13,14 whereas other researchers suggested that a familial history of BU was associated with an increased risk of BU.11,12 It is thought that host genetic factors may influence individual susceptibility to the development of BU after exposure to M ulcerans.15 Therefore, a genetic predisposition might explain why some members of the family described herein who had a similar risk of exposure to the pathogenic organism did not develop BU.

In the endemic areas, M ulcerans has been detected from diverse environmental samples, such as soil, sediment, water bugs, and mosquitoes.1,2,9 We detected IS2404 from the crayfish captured in a water channel surrounding the house of our patients. However, direct transmission from crayfish is unlikely because of the location of the patients’ lesions. Detection of IS2404 from crayfish indicates the possibility that, similar to endemic areas, aquatic environments act as a reservoir of the pathogenic strain in Japan. Like other Japanese patients, our patients developed skin lesions in the winter. Considering the latent period of M ulcerans, which is estimated to be several months or longer,9,16 it is conceivable that our patients were infected with the pathogen in the summer and developed skin lesions after an incubation period of several months. If such a latency is true, aquatic insects, such as mosquitoes and blackflies, which become active and bite humans during the summer, may be possible vectors in Japan. Further investigation is needed to clarify the transmission pathway to prevent this serious infectious disease.

ARTICLE INFORMATION

Corresponding Author: Mikio Ohtsuka, MD, Department of Dermatology, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima 960-1295, Japan (motsuka@fmu.ac.jp).

Accepted for Publication: July 10, 2013.

Published Online: November 6, 2013. doi:10.1001/jamadermatol.2013.6816.

Author Contributions: Drs Ohtsuka and Ishii had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Ohtsuka, Kikuchi, Yamamoto, Nakanaga, Suzuki, Ishii.

Acquisition of data: All authors.

Analysis and interpretation of data: All authors.

Drafting of the manuscript: Ohtsuka, Kikuchi, Yamamoto, Suzuki, Ishii.

Critical revision of the manuscript for important intellectual content: Yamamoto, Suzutani, Nakanaga, Suzuki, Ishii.

Administrative, technical, and material support: Suzutani, Nakanaga, Suzuki, Ishii.

Study supervision: Yamamoto, Suzuki, Ishii.

Conflict of Interest Disclosures: None reported.

Additional Contributions: Masaaki Ito, MD, and colleagues treated our patients after the 2011 Tōhoku, Japan, earthquake and tsunami. Kyoko Nishiyama assisted with the culture and identification of pathogenic organisms.

REFERENCES

van der Werf  TS, van der Graaf  WT, Tappero  JW, Asiedu  K.  Mycobacterium ulcerans infection. Lancet. 1999;354(9183):1013-1018.
PubMed   |  Link to Article
Merritt  RW, Walker  ED, Small  PL,  et al.  Ecology and transmission of Buruli ulcer disease: a systematic review. PLoS Negl Trop Dis. 2010;4(12):e911. http://ncbi.nlm.nih.gov/pmc/articles/PMC3001905/. Accessed September 28, 2013.
PubMed   |  Link to Article
World Health Organization Media Centre. Buruli ulcer (Mycobacterium ulcerans infection). Fact sheet 199. Updated June 2013. http://who.int/mediacentre/factsheets/fs199/en/. Accessed October 1, 2013.
Mikoshiba  H, Shindo  Y, Matsumoto  H, Mochizuki  M, Tsukamura  M.  A case of typical mycobacteriosis due to Mycobacterium ulcerans–like organism [in Japanese]. Nihon Hifuka Gakkai Zasshi. 1982;92(5):557-565.
PubMed
Stinear  TP, Hong  H, Frigui  W,  et al.  Common evolutionary origin for the unstable virulence plasmid pMUM found in geographically diverse strains of Mycobacterium ulcerans. J Bacteriol. 2005;187(5):1668-1676.
PubMed   |  Link to Article
Yotsu  RR, Nakanaga  K, Hoshino  Y, Suzuki  K, Ishii  N.  Buruli ulcer and current situation in Japan: a new emerging cutaneous Mycobacterium infection. J Dermatol. 2012;39(7):587-593.
PubMed   |  Link to Article
Nakanaga  K, Ishii  N, Suzuki  K,  et al.  ”Mycobacterium ulcerans subsp. shinshuense” isolated from a skin ulcer lesion: identification based on 16S rRNA gene sequencing. J Clin Microbiol. 2007;45(11):3840-3843.
PubMed   |  Link to Article
Suzuki  K, Takigawa  W, Tanigawa  K,  et al.  Detection of Mycobacterium leprae DNA from archaeological skeletal remains in Japan using whole genome amplification and polymerase chain reaction. PLoS One. 2010;5(8):e12422. http://ncbi.nlm.nih.gov/pmc/articles/PMC2928730/. Accessed September 28, 2013.
PubMed   |  Link to Article
Walsh  DS, Portaels  F, Meyers  WM.  Buruli ulcer: advances in understanding Mycobacterium ulcerans infection. Dermatol Clin. 2011;29(1):1-8.
PubMed   |  Link to Article
Nakanaga  K, Hoshino  Y, Yotsu  RR, Makino  M, Ishii  N.  Nineteen cases of Buruli ulcer diagnosed in Japan from 1980 to 2010. J Clin Microbiol. 2011;49(11):3829-3836.
PubMed   |  Link to Article
Sopoh  GE, Barogui  YT, Johnson  RC,  et al.  Family relationship, water contact and occurrence of Buruli ulcer in Benin. PLoS Negl Trop Dis. 2010;4(7):e746. http://ncbi.nlm.nih.gov/pmc/articles/PMC2903473/. Accessed September 28, 2013.
PubMed   |  Link to Article
Aiga  H, Amano  T, Cairncross  S, Adomako  J, Nanas  OK, Coleman  S.  Assessing water-related risk factors for Buruli ulcer: a case-control study in Ghana. Am J Trop Med Hyg. 2004;71(4):387-392.
PubMed
Raghunathan  PL, Whitney  EA, Asamoa  K,  et al.  Risk factors for Buruli ulcer disease (Mycobacterium ulcerans infection): results from a case-control study in Ghana. Clin Infect Dis. 2005;40(10):1445-1453.
PubMed   |  Link to Article
Nackers  F, Johnson  RC, Glynn  JR, Zinsou  C, Tonglet  R, Portaels  F.  Environmental and health-related risk factors for Mycobacterium ulcerans disease (Buruli ulcer) in Benin. Am J Trop Med Hyg. 2007;77(5):834-836.
PubMed
Stienstra  Y, van der Werf  TS, Oosterom  E,  et al.  Susceptibility to Buruli ulcer is associated with the SLC11A1 (NRAMP1) D543N polymorphism. Genes Immun. 2006;7(3):185-189.
PubMed   |  Link to Article
Jacobsen  KH, Padgett  JJ.  Risk factors for Mycobacterium ulcerans infection. Int J Infect Dis. 2010;14(8):e677-e681. http://ijidonline.com/article/S1201-9712(10)00031-7/abstract. Accessed September 28, 2013.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Clinical and Histological Features of Case 1

A, A red indurated lesion with a central ulcer on the right cheek. B, The skin biopsy specimen of a facial lesion showing extensive necrosis of deep dermis and subcutaneous fat. Inflammatory infiltrates are observed only scarcely (hematoxylin-eosin, original magnification ×100). C, A slightly red indurated plaque with a small central ulcer on the left leg. D, Numerous acid-fast bacilli detected by Ziehl-Neelsen stain of the biopsy specimen of a leg lesion (original magnification ×400).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Clinical Features of Case 2 and Case 3

A, A slightly red indurated plaque with a small necrotic ulcer on the right arm of case 2. B, A red indurated plaque with central concavity on the right wrist of case 3.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  16S Ribosomal RNA Gene Sequences Differentiating Mycobacterium ulcerans and Related Species

References

van der Werf  TS, van der Graaf  WT, Tappero  JW, Asiedu  K.  Mycobacterium ulcerans infection. Lancet. 1999;354(9183):1013-1018.
PubMed   |  Link to Article
Merritt  RW, Walker  ED, Small  PL,  et al.  Ecology and transmission of Buruli ulcer disease: a systematic review. PLoS Negl Trop Dis. 2010;4(12):e911. http://ncbi.nlm.nih.gov/pmc/articles/PMC3001905/. Accessed September 28, 2013.
PubMed   |  Link to Article
World Health Organization Media Centre. Buruli ulcer (Mycobacterium ulcerans infection). Fact sheet 199. Updated June 2013. http://who.int/mediacentre/factsheets/fs199/en/. Accessed October 1, 2013.
Mikoshiba  H, Shindo  Y, Matsumoto  H, Mochizuki  M, Tsukamura  M.  A case of typical mycobacteriosis due to Mycobacterium ulcerans–like organism [in Japanese]. Nihon Hifuka Gakkai Zasshi. 1982;92(5):557-565.
PubMed
Stinear  TP, Hong  H, Frigui  W,  et al.  Common evolutionary origin for the unstable virulence plasmid pMUM found in geographically diverse strains of Mycobacterium ulcerans. J Bacteriol. 2005;187(5):1668-1676.
PubMed   |  Link to Article
Yotsu  RR, Nakanaga  K, Hoshino  Y, Suzuki  K, Ishii  N.  Buruli ulcer and current situation in Japan: a new emerging cutaneous Mycobacterium infection. J Dermatol. 2012;39(7):587-593.
PubMed   |  Link to Article
Nakanaga  K, Ishii  N, Suzuki  K,  et al.  ”Mycobacterium ulcerans subsp. shinshuense” isolated from a skin ulcer lesion: identification based on 16S rRNA gene sequencing. J Clin Microbiol. 2007;45(11):3840-3843.
PubMed   |  Link to Article
Suzuki  K, Takigawa  W, Tanigawa  K,  et al.  Detection of Mycobacterium leprae DNA from archaeological skeletal remains in Japan using whole genome amplification and polymerase chain reaction. PLoS One. 2010;5(8):e12422. http://ncbi.nlm.nih.gov/pmc/articles/PMC2928730/. Accessed September 28, 2013.
PubMed   |  Link to Article
Walsh  DS, Portaels  F, Meyers  WM.  Buruli ulcer: advances in understanding Mycobacterium ulcerans infection. Dermatol Clin. 2011;29(1):1-8.
PubMed   |  Link to Article
Nakanaga  K, Hoshino  Y, Yotsu  RR, Makino  M, Ishii  N.  Nineteen cases of Buruli ulcer diagnosed in Japan from 1980 to 2010. J Clin Microbiol. 2011;49(11):3829-3836.
PubMed   |  Link to Article
Sopoh  GE, Barogui  YT, Johnson  RC,  et al.  Family relationship, water contact and occurrence of Buruli ulcer in Benin. PLoS Negl Trop Dis. 2010;4(7):e746. http://ncbi.nlm.nih.gov/pmc/articles/PMC2903473/. Accessed September 28, 2013.
PubMed   |  Link to Article
Aiga  H, Amano  T, Cairncross  S, Adomako  J, Nanas  OK, Coleman  S.  Assessing water-related risk factors for Buruli ulcer: a case-control study in Ghana. Am J Trop Med Hyg. 2004;71(4):387-392.
PubMed
Raghunathan  PL, Whitney  EA, Asamoa  K,  et al.  Risk factors for Buruli ulcer disease (Mycobacterium ulcerans infection): results from a case-control study in Ghana. Clin Infect Dis. 2005;40(10):1445-1453.
PubMed   |  Link to Article
Nackers  F, Johnson  RC, Glynn  JR, Zinsou  C, Tonglet  R, Portaels  F.  Environmental and health-related risk factors for Mycobacterium ulcerans disease (Buruli ulcer) in Benin. Am J Trop Med Hyg. 2007;77(5):834-836.
PubMed
Stienstra  Y, van der Werf  TS, Oosterom  E,  et al.  Susceptibility to Buruli ulcer is associated with the SLC11A1 (NRAMP1) D543N polymorphism. Genes Immun. 2006;7(3):185-189.
PubMed   |  Link to Article
Jacobsen  KH, Padgett  JJ.  Risk factors for Mycobacterium ulcerans infection. Int J Infect Dis. 2010;14(8):e677-e681. http://ijidonline.com/article/S1201-9712(10)00031-7/abstract. Accessed September 28, 2013.
PubMed   |  Link to Article

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