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Clinical Updates

Antoine Petit, MD

Buruli Ulcer

Antoine Petit

Wednesday, December 10, 2008

Buruli ulcers illustrate the importance of skin infections among public health concerns in developing countries. The disease is due to skin and soft tissue invasion by Mycobacterium ulcerans. It is seldom lethal by itself, but highly destructive, leading to extensive tissue loss that causes severe functional, aesthetic, psychological and socioeconomical disabilities. Although it has been recognized for more than one century, Buruli ulcers only got sufficient interest from the medical community and health authorities after a solemn commitment of the World Health Organization in 19981. The following ten years were marked by substantial progress in the basic knowledge of M. ulcerans, as well as the development of diagnostic and therapeutic tools for this time-neglected disease2.

Etiology

The genome sequence of Mycobacterium ulcerans has now been completely determined3. The micro-organism is closely related to M. marinum, with a unique distinguishing feature: it produces mycolactones, a family of macrolide toxins. Mycolactones are responsible for microbial invasion and tissue necrosis; they inhibit the immune and inflammatory responses to the mycobacteria and seem crucial to the painlessness that typically characterizes the infected soft tissues4. The unequal virulence properties of various strains of M. ulcerans (eg, less aggressivity of the Australian strains compared with the African ones) probably lies on their distinct patterns of mycolactone production5,6.

Epidemiology and transmission

Buruli ulcer owes its name to a pocket of infection that took place during the 1960s in the district of Nakasongola, formerly known as Buruli county, in Uganda. Indeed, most cases come from Western and Central sub-Saharan Africa. About 1000 to 2000 cases are reported annually from each of the three main endemic areas: Ivory Coast, Benin, and Ghana1. The global prevalence of Buruli ulcer is approximately 20 in 100,000 in these countries but can reach up to 16% in some villages6. In addition, the disease has been observed in at least 30 tropical or subtropical countries in Africa, Central and South-America,  South-East Asia7 and Australasia.  As Buruli ulcer has only recently gained real attention from the health authorities,  it is difficult to comment about a hypothetic increase in its prevalence; the disease is probably under-reported and a new endemic focus may still be disclosed in the future. The only involved temperate area is the state of Victoria in Australia, including the city of Bairnsdale where M. ulcerans was first recovered from a patient in 1948.

About half of the patients are children between 5 and 15 years of age, without gender predilection. The disease is focally distributed in small clusters, but there is no case of human to human transmission. Actually, living near stagnant or slow-flowing water appears to represent the main risk factor1,2. Indirect evidence for the presence of M. ulcerans in aquatic environments was brought about by molecular analysis of water, sediments, plants and small animals. In particular, the micro-organism has the ability to invade the salivary glands of carnivorous water bugs and the biofilm surrounding their feeding pincers, which then infect mice that have been bitten by these insects2. In Australia, the possibility of mosquito bites being involved in the transmission of M. ulcerans to humans has been suggested8,9. Finally, environmental M. ulcerans was first cultivated and characterized from a water bug of Gerrida sp. (a kind of insect that does not usually bite humans) gathered in Benin10. As attractive as the insect bite hypothesis may seem, prolonged contact of the skin with contaminated muddy fields1 could be involved as well. In summary, the route of M. ulcerans transmission from the aquatic environment to the human, and its potential reservoirs, remains to be elucidated1,11.

Clinical Manifestations

Buruli ulcer typically begins as a single painless mobile subcutaneous nodule that is usually located on the lower or upper limbs, but may arise on any part of the integument. Less typical cases present as a diffuse non-inflammatory (cold) edema, plaques or multiple papules. The lesion then breaks down to form an ulcer that slowly enlarges, giving the characteristic appearence of a wide loss of substance with deep undermined edges. There is usually no fever and no pain;  however, pain may occur, especially in cases of bacterial superinfection. The necrosis of the soft tissues progresses for months and years and sometimes reaches the underlying bone or joint, or even more critical organs such as the eyes or genitalia.  Systemic infection, malnutrition and even squamous cell carcinoma may complicate the course of the disease. Spontaneous healing occurs after months or years, leaving fibrotic scars that compromise the function of the affected organ or limb.

The risk and severity of M. ulcerans depends on several factors. A potential aggravating role for HIV co-infection has been debated1,6; in Benin, the prevalence of HIV seropositivity appears to be higher in patients with Buruli ulcer than in a control group12.

Diagnosis

In many developing countries, the positive diagnosis of Buruli ulcer mostly relies on physical examination. Direct microscopic examination of smears from ulcer swabs or skin biopsies (Ziehl-Neelsen stain) is the most available laboratory test, but lacks sensitivity. Swabs and biopsies may allow the growth of M. ulcerans at 30-33°C in a Löwenstein-Jensen medium; however, the procedure is costly and usually takes 6 to 8 weeks. Histological examination of a tissue biopsy is credited with a 90% sensitivity. Polymerase Chain Reaction (PCR), with amplification of the characteristic IS2404 repetitive sequence of M. ulcerans DNA, is even more sensitive and highly specific, and gives fast results in less than 24 hours. However, PCR and histology are usually unavailable or difficult to implement in the field. The development of new diagnostic tools that can be used in endemic areas is now a priority for researchers1,6.

Differential diagnosis depends on the stage and type of lesion. Various infectious diseases may be considered: soft tissue tuberculosis; deep mycosis; and benign or malignant tumors13.

Treatment

Although M. ulcerans has been shown to be susceptible in vitro to a variety of antibiotics14, the treatment has long been exclusively based on a wide surgical excision, which is still mandatory in most ulcerated lesions1,6.  Prolonged stays in hospital, physiotherapy, long-lasting wound dressings and other nursing care are frequently required after surgery.

Promising preliminary results were obtained with a 4- to 12-week regimen of oral rifampicin (10 mg/kg/day) combined with intramuscular streptomycin (15 mg/kg/day) in 16 out of 21 patients with early lesions (diameter <10 cm)15. These results, together with in vitro studies, prompted the World Health Organization to publish guidelines for a systematic first-line medical treatment for 8 weeks for these antibiotics. An open-label trial of this treatment in Benin (n = 224) showed an elevated cure rate of 47% with antibiotics alone, especially for early lesions (< 5 cm diameter), and also suggested a protective effect against recurrence after surgical excision in more advanced stages16. This regimen remains to be accurately evaluated in comparison to other antimicrobial agents. There are also some concerns regarding the risk of selecting resistant strains of M. tuberculosis with rifampicin therapy, the choice of a parenteral route of administration in the setting of HIV endemics and the long-term tolerance of streptomycin6. Finally, the potential role of heparin in improving antibiotic penetration at the lesional site should also be evaluated6,13.

Prevention 

Neither environmental nor individual preventive measures can yet be defined, because the mode of transmission of M. ulcerans to human and its potential  intermediary hosts are still largely unknown. However, public information and education remain critical, especially for an early diagnosis of  the disease,  which may allow a medical cure with limited, if any, residual disabilities. A good understanding of the knowledge, beliefs and attitudes of exposed populations towards Buruli ulcer is mandatory for targeting information campaigns1,6.

It appears that BCG vaccination may offer a moderate protection against M. ulcerans infection1,6,17. However, a more efficient vaccine would provide an essential advance in the control of  the disease.

Conclusion

Public health measures against Buruli ulcer are still waiting for a precise understanding of the way in which humans get infected by this organism from the environment. Nevertheless, dramatic progress has been made since 1998 in the comprehension and management of this disease, bringing hope for hundreds of thousands of children around the world. In particular, sequencing the entire genome of the micro-organism could now allow the development of specific treatments or vaccines17 targeted against mycolactones or other components of M. ulcerans.

References

  1. Anonymous. Buruli ulcer: progress report, 2004-2008. Wkly Epidemiol Rec 2008;83(17):145-54.
  2. Wansbrough-Jones M, Phillips R. Buruli ulcer: emerging from obscurity. Lancet 2006;367(9525):1849-58.
  3. Stinear TP, Seemann T, Pidot S, et al. Reductive evolution and niche adaptation inferred from the genome of Mycobacterium ulcerans, the causative agent of Buruli ulcer. Genome Res. 2007;17(2):192-200.
  4. En J, Goto M, Nakanaga K, Higashi M, et al. Mycolactone is responsible for the painlessness of Mycobacterium ulcerans infection (buruli ulcer) in a murine study. Infect Immun. 2008;76(5):2002-7. 
  5. van der Werf TS, Stinear T, Stienstra Y, et al. Mycolactones and Mycobacterium ulcerans disease. Lancet. 2003;362(9389):1062-4.
  6. Sizaire V, Nackers F, Comte E, Portaels F. Mycobacterium ulcerans infection: control, diagnosis, and treatment. Lancet Infect Dis. 2006;6(5):288-96.
  7. 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. Clin Microbiol. 2007;45(11):3840-3. 
  8. Johnson PD, Azuolas J, Lavender CJ, et al. Mycobacterium ulcerans in mosquitoes captured during outbreak of Buruli ulcer, southeastern Australia. Emerg Infect Dis. 2007;13(11):1653-60.
  9. Quek TY, Athan E, Henry MJ, et al. Risk factors for Mycobacterium ulcerans infection, southeastern Australia. Emerg Infect Dis. 2007;13(11):1661-6.
  10. Portaels F, Meyers WM, Ablordey A, et al. First cultivation and characterization of Mycobacterium ulcerans from the environment. PLoS Negl Trop Dis. 2008;2(3):e178.
  11. Stinear T, Johnson PD. First isolation of Mycobaterium ulcerans from an aquatic environment: The end of a 60-year search? PLoS Negl Trop Dis. 2008;2(3):e216.
  12. Johnson RC, Nackers F, Glynn JR, et al. Association of HIV infection and Mycobacterium ulcerans disease in Benin. AIDS. 2008;22(7):901-3.
  13. Kanga JM, Kacou ED, Kouamé K, et al. La lutte contre l'ulcère de Buruli. Expérience de la Côte d'Ivoire. Bull Soc Pathol Exot. 2006;99(1):34-8.
  14. Ji B, Chauffour A, Robert J, Jarlier V. Bactericidal and sterilizing activities of several orally administered combined regimens against Mycobacterium ulcerans in mice. Antimicrob Agents Chemother. 2008;52(6):1912-6. 
  15. Etuaful S, Carbonnelle B, Grosset J, et al. Efficacy of the combination rifampin-streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans. Antimicrob Agents Chemother. 2005;49(8):3182-6.
  16. Chauty A, Ardant MF,  Adeye A, et al. Promising clinical efficacy of streptomycin-rifampin combination for treatment of Buruli ulcer (Mycobacterium ulcerans disease). Antimicrob Agents Chemother. 2007;51(11):4029-35.
  17. Tanghe A, Dangy JP, Pluschke G, Huygen K. Improved protective efficacy of a species-specific DNA vaccine encoding mycolyl-transferase Ag85A from Mycobacterium ulcerans by homologous protein boosting. PLoS Negl Trop Dis. 2008;2(3):e199.
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