Buruli ulcer
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《英国医生杂志》
A neglected but treatable disease that unnecessarily scars African children for life
Buruli ulcer, caused by infection with Mycobacterium ulcerans, is unfamiliar because it is common only among children in rural tropical areas, mainly in west Africa. Ghana, C?te d'Ivoire, and Benin are among the worst affected.1 It is named Buruli after a county in Uganda. It is an easily treatable disease as common as tuberculosis in areas where it is endemic.w1 In endemic areas in Ghana point prevalence has been estimated at 150-180/100 000 population, and in southern Benin, a detection rate of 20/100 000 per year has been reported.w2 w3 Lack of treatment leaves children with large disfiguring scars and occasionally with joint deformities, loss of sight, loss of breast or scrotal tissue, and even amputations.
Ulcers (figure) can reach a dramatic size, particularly in the oedematous form, which spreads rapidly over large parts of the limbs, trunk, or head. How infection is transmitted remains a mystery; it may be through infection of simple grazes on the skin by water from rivers, ponds, or even mud, the rainy season being the time when most infections occur. Water insects (Naucoridae and Belostomatidae) have been incriminated, but their bites have not yet been shown to transmit infection to humans. Water insects from rivers in C?te d'Ivoire can bite and infect mouse tails in the laboratory, but M ulcerans has not been cultured directly from the environment.2 Ongoing studies of differences in environmental water between endemic and non-endemic areas may shed more light on the highly focal epidemiology of the disease.
Buruli ulcer on the knee of an 8 year old Ghanaian boy
M ulcerans replicates in subcutaneous tissue where the temperature approaches the optimum of 30-33°C for in vitro culture. It was first cultured in Melbourne in 1947 when an incubator broke down and the temperature dropped to this level, leading eventually to the establishment of a link between the organism and the disease known there as Bairnsdale ulcer.w4
Why temperate southeastern Australia should be the exception in its epidemiology is a mystery, but researchers in that country have taken a lead in investigating the problem. They have recently collaborated in sequencing the genome of M ulcerans,3 which takes us to the heart of what makes it unique among mycobacteria. It causes disease through production of a potent tissue destructive toxin called mycolactone.4 This toxic macrolide prevents phagocytosis of live organisms and may delay the development of an inflammatory response as well as causing cell death by apoptosis.5
Infected subcutaneous tissue shows extensive fatty necrosis with numerous clumps of extracellular mycobacteria but no inflammatory reaction in the immediate vicinity.w5 Detailed study of the genome has found that mycolactone is encoded by genes for three polyketide synthases and other enzymes on two identical copies of a plasmid separate from the main DNA sequence.6 Further work will possibly generate ways of inhibiting the toxin itself or pathways involved in its production. Knowledge of the genome should increase understanding of the molecular biology of the organism, leading perhaps to revelation of the mode of transmission of infection and the possibility of developing vaccines.
Traditionally treatment has relied on complete excision of infected tissue, but we now know that normal looking skin around a lesion contains organisms. As access to surgery in rural tropical areas is problematic the focus is shifting to treatment with rifampicin and streptomycin combined with much smaller surgical intervention. Years of in vitro and animal model studies have established this combination of antibiotics as the most effective way of killing M ulcerans, and more recent work shows that the organisms can be killed in human tissue by treatment for at least four weeks.7 8 A prospective but uncontrolled study of patients in Benin according to guidelines from the World Health Organization has shown that most are cured by treatment with rifampicin and streptomycin for eight weeks with less than 3% recurrences.9
If inhibition of mycolactone production alone is sufficient to allow the immune response to control infection in humans is not known, but evidence shows that nearly one third of early lesions heal without any treatment.10 A superficial infection, Buruli ulcer may be susceptible to topical treatment alone. Creams generating topical nitrogen oxide promoted healing in one small study, and nitric oxide killed M ulcerans in vitro.11 12 Phenytoin powder probably does not kill the organism, but it seemed to promote healing, perhaps through acceleration of fibrogenesis.w6
Future research needs to concentrate on three main areas—the mode of transmission of the disease; the effectiveness of antibiotics and the best way of using them; and characterisation of proteins specific to M ulcerans through knowledge of the genome sequence in order to develop an effective vaccine.
Mark Wansbrough-Jones, consultant physician
St George's Hospital Medical School, London SW17 0RE
(wansbrou@sghms.ac.uk)
Richard Phillips, Wellcome Trust research fellow
St George's Hospital Medical School, London SW17 0RE
Additional references w1-w6 are on bmj.com
Competing interests: None declared.
References
Asiedu K, Scherpbier R, Raviglione M. Buruli ulcer: Mycobacterium ulcerans infection. Geneva: World Health Organization, 2000. www.who.int/gtb-buruli/publications/PDF/Buruli_ulcer_monograph.PDF (accessed 21 Apr 2005).
Marsollier L, Aubry J, Saint-Andre JP, Robert R, Legras P, Manceau AL, et al. . Pathol Biol (Paris) 2003;51: 490-5.
Stinear TP. The complete genome sequence of Mycobacterium ulcerans strain Agy99. Report of the 8th annual WHO advisory group meeting on Buruli ulcer. 2005. (In press.)
George KM, Chatterjee D, Gunawardana G, Welty D, Hayman J, Lee R, et al. Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence. Science 1999;283: 854-7.
George KM, Pascopella L, Welty DM, Small PL. A Mycobacterium ulcerans toxin, mycolactone, causes apoptosis in guinea pig ulcers and tissue culture cells. Infect Immun 2000;68: 877-83.
Stinear TP, Mve-Obiang A, Small PL, Frigui W, Pryor MJ, Brosch R, et al. Giant plasmid-encoded polyketide synthases produce the macrolide toxin of Mycobacterium ulcerans. Proc Natl Acad Sci USA 2004;101: 1345-9.
Dega H, Bentoucha A, Robert J, Jarlier V, Grosset J. Bactericidal activity of rifampin-amikacin against Mycobacterium ulcerans in mice. Antimicrob Agents Chemother 2002;46: 3193-6.
Etuaful S, Carbonnelle B, Grosset J, Lucas S, Horsefield C, Phillips R, et al. Bactericidal activity of rifampicin and streptomycin treatment for early human M. ulcerans lesions. Report of the 7th Annual WHO Advisory Group Meeting on Buruli ulcer. 2004. p110. www.who.int/gtb-buruli/publications/PDF/WHO-CDS-CPE-GBUI-2004.9.pdf (accessed 21 Apr 2005).
Chauty A. Drug treatment in Benin. Report of the 8th Annual WHO Advisory Group Meeting on Buruli ulcer. 2005. (In press.)
Revill WD, Morrow RH, Pike MC, Ateng J. A controlled trial of the treatment of Mycobacterium ulcerans infection with clofazimine. Lancet 1973;2: 873-7.
Phillips R, Adjei O, Lucas S, Benjamin N, Wansbrough-Jones M. Pilot randomized double-blind trial of treatment of Mycobacterium ulcerans disease (Buruli ulcer) with topical nitrogen oxides. Antimicrob Agents Chemother 2004;48: 2866-70.
Phillips R, Kuijper S, Benjamin N, Wansbrough-Jones M, Wilks M, Kolk AH. In vitro killing of Mycobacterium ulcerans by acidified nitrite. Antimicrob Agents Chemother 2004;48: 3130-2.
Buruli ulcer, caused by infection with Mycobacterium ulcerans, is unfamiliar because it is common only among children in rural tropical areas, mainly in west Africa. Ghana, C?te d'Ivoire, and Benin are among the worst affected.1 It is named Buruli after a county in Uganda. It is an easily treatable disease as common as tuberculosis in areas where it is endemic.w1 In endemic areas in Ghana point prevalence has been estimated at 150-180/100 000 population, and in southern Benin, a detection rate of 20/100 000 per year has been reported.w2 w3 Lack of treatment leaves children with large disfiguring scars and occasionally with joint deformities, loss of sight, loss of breast or scrotal tissue, and even amputations.
Ulcers (figure) can reach a dramatic size, particularly in the oedematous form, which spreads rapidly over large parts of the limbs, trunk, or head. How infection is transmitted remains a mystery; it may be through infection of simple grazes on the skin by water from rivers, ponds, or even mud, the rainy season being the time when most infections occur. Water insects (Naucoridae and Belostomatidae) have been incriminated, but their bites have not yet been shown to transmit infection to humans. Water insects from rivers in C?te d'Ivoire can bite and infect mouse tails in the laboratory, but M ulcerans has not been cultured directly from the environment.2 Ongoing studies of differences in environmental water between endemic and non-endemic areas may shed more light on the highly focal epidemiology of the disease.
Buruli ulcer on the knee of an 8 year old Ghanaian boy
M ulcerans replicates in subcutaneous tissue where the temperature approaches the optimum of 30-33°C for in vitro culture. It was first cultured in Melbourne in 1947 when an incubator broke down and the temperature dropped to this level, leading eventually to the establishment of a link between the organism and the disease known there as Bairnsdale ulcer.w4
Why temperate southeastern Australia should be the exception in its epidemiology is a mystery, but researchers in that country have taken a lead in investigating the problem. They have recently collaborated in sequencing the genome of M ulcerans,3 which takes us to the heart of what makes it unique among mycobacteria. It causes disease through production of a potent tissue destructive toxin called mycolactone.4 This toxic macrolide prevents phagocytosis of live organisms and may delay the development of an inflammatory response as well as causing cell death by apoptosis.5
Infected subcutaneous tissue shows extensive fatty necrosis with numerous clumps of extracellular mycobacteria but no inflammatory reaction in the immediate vicinity.w5 Detailed study of the genome has found that mycolactone is encoded by genes for three polyketide synthases and other enzymes on two identical copies of a plasmid separate from the main DNA sequence.6 Further work will possibly generate ways of inhibiting the toxin itself or pathways involved in its production. Knowledge of the genome should increase understanding of the molecular biology of the organism, leading perhaps to revelation of the mode of transmission of infection and the possibility of developing vaccines.
Traditionally treatment has relied on complete excision of infected tissue, but we now know that normal looking skin around a lesion contains organisms. As access to surgery in rural tropical areas is problematic the focus is shifting to treatment with rifampicin and streptomycin combined with much smaller surgical intervention. Years of in vitro and animal model studies have established this combination of antibiotics as the most effective way of killing M ulcerans, and more recent work shows that the organisms can be killed in human tissue by treatment for at least four weeks.7 8 A prospective but uncontrolled study of patients in Benin according to guidelines from the World Health Organization has shown that most are cured by treatment with rifampicin and streptomycin for eight weeks with less than 3% recurrences.9
If inhibition of mycolactone production alone is sufficient to allow the immune response to control infection in humans is not known, but evidence shows that nearly one third of early lesions heal without any treatment.10 A superficial infection, Buruli ulcer may be susceptible to topical treatment alone. Creams generating topical nitrogen oxide promoted healing in one small study, and nitric oxide killed M ulcerans in vitro.11 12 Phenytoin powder probably does not kill the organism, but it seemed to promote healing, perhaps through acceleration of fibrogenesis.w6
Future research needs to concentrate on three main areas—the mode of transmission of the disease; the effectiveness of antibiotics and the best way of using them; and characterisation of proteins specific to M ulcerans through knowledge of the genome sequence in order to develop an effective vaccine.
Mark Wansbrough-Jones, consultant physician
St George's Hospital Medical School, London SW17 0RE
(wansbrou@sghms.ac.uk)
Richard Phillips, Wellcome Trust research fellow
St George's Hospital Medical School, London SW17 0RE
Additional references w1-w6 are on bmj.com
Competing interests: None declared.
References
Asiedu K, Scherpbier R, Raviglione M. Buruli ulcer: Mycobacterium ulcerans infection. Geneva: World Health Organization, 2000. www.who.int/gtb-buruli/publications/PDF/Buruli_ulcer_monograph.PDF (accessed 21 Apr 2005).
Marsollier L, Aubry J, Saint-Andre JP, Robert R, Legras P, Manceau AL, et al. . Pathol Biol (Paris) 2003;51: 490-5.
Stinear TP. The complete genome sequence of Mycobacterium ulcerans strain Agy99. Report of the 8th annual WHO advisory group meeting on Buruli ulcer. 2005. (In press.)
George KM, Chatterjee D, Gunawardana G, Welty D, Hayman J, Lee R, et al. Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence. Science 1999;283: 854-7.
George KM, Pascopella L, Welty DM, Small PL. A Mycobacterium ulcerans toxin, mycolactone, causes apoptosis in guinea pig ulcers and tissue culture cells. Infect Immun 2000;68: 877-83.
Stinear TP, Mve-Obiang A, Small PL, Frigui W, Pryor MJ, Brosch R, et al. Giant plasmid-encoded polyketide synthases produce the macrolide toxin of Mycobacterium ulcerans. Proc Natl Acad Sci USA 2004;101: 1345-9.
Dega H, Bentoucha A, Robert J, Jarlier V, Grosset J. Bactericidal activity of rifampin-amikacin against Mycobacterium ulcerans in mice. Antimicrob Agents Chemother 2002;46: 3193-6.
Etuaful S, Carbonnelle B, Grosset J, Lucas S, Horsefield C, Phillips R, et al. Bactericidal activity of rifampicin and streptomycin treatment for early human M. ulcerans lesions. Report of the 7th Annual WHO Advisory Group Meeting on Buruli ulcer. 2004. p110. www.who.int/gtb-buruli/publications/PDF/WHO-CDS-CPE-GBUI-2004.9.pdf (accessed 21 Apr 2005).
Chauty A. Drug treatment in Benin. Report of the 8th Annual WHO Advisory Group Meeting on Buruli ulcer. 2005. (In press.)
Revill WD, Morrow RH, Pike MC, Ateng J. A controlled trial of the treatment of Mycobacterium ulcerans infection with clofazimine. Lancet 1973;2: 873-7.
Phillips R, Adjei O, Lucas S, Benjamin N, Wansbrough-Jones M. Pilot randomized double-blind trial of treatment of Mycobacterium ulcerans disease (Buruli ulcer) with topical nitrogen oxides. Antimicrob Agents Chemother 2004;48: 2866-70.
Phillips R, Kuijper S, Benjamin N, Wansbrough-Jones M, Wilks M, Kolk AH. In vitro killing of Mycobacterium ulcerans by acidified nitrite. Antimicrob Agents Chemother 2004;48: 3130-2.