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Buruli Ulcer
63
63
Buruli Ulcer Mark H. Wansbrough-Jones, Richard O. Phillips
KEY FEATURES • Mycobacterium ulcerans causes chronic skin ulcers, referred to as Buruli ulcers. • Common in parts of rural West Africa, but the mode of transmission is unknown. • Subcutaneous necrosis is caused by secretion of mycolactone toxin, a plasmid-encoded polyketide molecule. • Diagnosis is usually based on clinical recognition; polymerase chain reaction (PCR)–based analysis is also used. • Treatment includes 8 weeks of rifampin and clarithromycin. • Early recognition and treatment, including physiotherapy, can prevent disabilities.
INTRODUCTION Buruli ulcer is a neglected tropical disease caused by skin infection with Mycobacterium ulcerans. It is of considerable importance in rural parts of West and Central Africa, where it affects children and young adults and causes an economic burden on farming communities. Extensive ulceration is caused by a lipid toxin called mycolactone secreted by M. ulcerans, a pathogenesis not seen with other mycobacteria.
EPIDEMIOLOGY AND TRANSMISSION Buruli ulcer is a disease of high focal prevalence mainly within countries in West Africa (Fig. 63.1), but sporadic cases have been reported in many countries with high humidity in tropical wetlands. Buruli ulcer has been seen among people living in more than 30 countries around the world (Fig. 63.2), including French Guiana, Peru, Mexico, Papua New Guinea, Japan, and southern China. Outbreaks are also observed in temperate south eastern Australia, where the association of M. ulcerans with Buruli (Bairnsdale) ulcer was first recognized in 1948. Disturbance of water systems by mining, deforestation, or flooding has been associated with increased incidence of disease. Newly arrived migrants in endemic zones are susceptible to infection, as demonstrated by the occurrence of Buruli ulcer among displaced Rwandans in the Kinyara refugee camps in Uganda in the 1960s. These refugees had come from a non-endemic zone and developed ulcers within 4 to 10 weeks of arrival, suggesting the disease’s incubation period. M. ulcerans has been identified in skin lesions of wild koalas and ringtail possums in Australia and of mice in West Africa. It is difficult to culture, although it has been isolated from fresh water bugs in endemic zones after serial passage in mice.1 M. ulcerans probably exists in an ecologic niche related to slowflowing or stagnant water in West Africa, but how it is transmitted to humans remains unknown. Experimental evidence shows that it can be transmitted from infected water bugs to mice by biting.2 In Australia, DNA from M. ulcerans was detected in mosquitoes
from an affected area but not in mosquitoes from a non-infected area, as well as in possum feces; however, the significance of these observations is unclear. Buruli ulcer can affect people of all ages, but in West Africa it predominantly affects children aged 5 to 15 years, and in southeast Australia, it affects elderly residents in retirement towns.
CLINICAL PRESENTATION Most patients with Buruli ulcer present with a chronic ulcer, often of a few months’ duration. Patients fail to present early because the lesions are painless, and affected individuals often live in remote rural areas lacking easy access to affordable health care.3 The disease manifests as a 1- to 5-cm, painless, subcutaneous nodule attached to the overlying skin (Fig. 63.3A). In Australia, early lesions are often papular. More extensive indurated plaques may also occur, the margins of which are difficult to define. Nodules, plaques, and ulcers may be associated with edema in surrounding tissue (10%–15% in Ghana), which spreads outwards (Fig. 63.3B). Ulceration spreads from the initial lesion into edematous areas. The patient remains well, and there is no fever or pain unless secondary bacterial infection occurs. Occasionally, osteomyelitis occurs in bone adjacent to a skin lesion, but involvement of other organs is rare. The distinguishing features of Buruli ulcers are that they are painless and that the edges are undermined so that a swab can be pushed a few millimeters (or sometimes centimeters) under the surrounding skin (Fig. 63.3C). The ulcer border is not raised. Tissue destruction is caused by cytotoxic mycolactone toxin that also prevents the development of an inflammatory response.4 The process is chronic, and histologic examination of affected tissue often shows a mixture of scar formation; featureless necrosis around clumps of proliferating acid-fast mycobacteria; and acute, chronic, and granulomatous inflammation. Organisms are rarely seen within macrophages in untreated lesions, but careful immunohistologic studies have demonstrated that intracellular organisms can be observed during antibiotic treatment when the effect of mycolactone is lost.5 In 90% of cases, ulcers involve the limbs, but they can also involve the head, neck, or trunk. When scarring occurs close to a joint, there is often limitation of joint movement; large lesions on the trunk may inhibit spinal movement. Buruli ulcers recognize no anatomic boundaries and may involve critical sites, such as the face, breast, and genital area.
DIAGNOSIS Diagnosis is usually based on clinical recognition. Buruli ulcers on the lower extremities may be difficult to distinguish from diabetic or venous stasis ulcers. Acid-fast bacilli can be detected in about 40% of ulcers when a swab is taken from the base, close to undermined areas. Cultures (on Löwenstein–Jensen medium at 32°C) are more sensitive (up to 60% positive), yielding mycobacterial growth when performed in a laboratory near the endemic area, but it can take 6 weeks or more for mycobacterial growth to be detectable. Histologic examination can be 85% sensitive but is not available in many endemic areas. The most sensitive diagnostic test (98%) is polymerase chain reaction (PCR) for the
565
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PART 3 Bacterial Infections
Fig. 63.1 Buruli ulcer incidence in Ghana during 2008. (Map created by Julie Clennon, Rollins School of Public Health, from data provided by Edwin Ampadu and William Opare, Ghana National BU Control Programme. Funded by National Institute of Environmental Health Sciences grants #R01ES015525 and #T32ES012160.)
Number of reported cases, 2016 ≥500
No cases reported
300–499
Previously reported cases
100–299
Not applicable
<100 Fig. 63.2 New cases of Buruli ulcer reported to the WHO in 2016. (Provided by Dr. Kingsley Asiedu, WHO.)
CHAPTER 63 Buruli Ulcer
567
63
A
B
C Fig. 63.3 Clinical forms of Buruli ulcer disease. (A) Subcutaneous, firm, painless nodule attached to the skin. (B) Extensive edema of the left arm and leg and genitalia with ulceration on the left arm and knee. (C) Partially debrided ulcer on the right knee with further ulceration on the leg and foot. All the ulcers were probably connected subcutaneously.
IS2404 repeat sequence of M. ulcerans. PCR can be applied to swabs, punch biopsies (3–4 mm diameter), and fine needle aspirates. The latter approaches may be helpful in diagnosing individual nodules, plaques, and edematous lesions that have not yet ulcerated.6
release up to a maximum of 500 mg orally twice a day for 8 weeks. Fluoroquinolone antibiotics also have some activity. The standard dressing is gauze coated with Vaseline which is changed daily. Most lesions heal without surgical intervention, but occasionally debridement and split-skin grafting are needed for large ulcers.
MANAGEMENT
COMPLICATIONS
Daily treatment under observation with rifampin 10 mg/kg (up to 600 mg per day) orally and streptomycin 15 mg/kg intramuscularly for 8 weeks results in healing of all forms of M. ulcerans disease with few exceptions.7 Recurrence after antibiotic treatment is rare (0%–2.5%). A controlled trial has shown that clarithromycin can be substituted for streptomycin in the second 4 weeks of treatment without loss of efficacy,8 and recently a controlled trial comparing rifampin plus clarithromycin for 8 weeks with rifampin plus streptomycin for 8 weeks has been completed. Preliminary results show equivalent results for the fully oral regimen, and because streptomycin is no longer available routinely, the World Health Organization (WHO) expert advisors have now recommended rifampin 10 mg/kg (up to maximum 600 mg daily) orally combined with clarithromycin 15 mg/kg orally daily if extended release preparation, or divided into two doses if not extended
Chronic ulceration leads to disfiguring scars and significant loss of tissue. Extensive ulcers on the limbs sometimes require amputation, particularly when there is concurrent osteomyelitis. Secondary bacterial infection of a Buruli ulcer may cause life-threatening septicemia. Paradoxical reactions, characterized by increased inflammation and lesion size or the appearance of new lesions, occur in up to 10% of patients. A fluctuant mass may appear close to the initial lesion during antibiotic treatment, and purulent discharge that is usually sterile can be aspirated. These lesions resolve without additional antibiotic treatment. When a Buruli ulcer is close to a joint, there may be limitation of joint movement and an increased risk of scarring. Functional limitation can be prevented by simple physiotherapy that can be taught to the patient and family when treatment is started.
568
PART 3 Bacterial Infections
PREVENTION Understanding how M. ulcerans infection is transmitted to humans is a priority, as this information could lead to preventive strategies. Epidemiologic studies have shown that exposure to water sources near endemic villages is a risk factor for developing Buruli ulcer, but reducing exposure, particularly of children, to such sources is impractical in rural West Africa. No effective vaccine is currently available, although Bacillus Calmette–Guérin (BCG) vaccine has been associated with shortlived protection in small trials. Outreach programs to educate communities in endemic areas to recognize early Buruli lesions is vital for prevention of severe forms of the disease. REFERENCES
1. 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. 2. Marsollier L, Robert R, Aubry J, et al. Aquatic insects as a vector for Mycobacterium ulcerans. Appl Environ Microbiol 2002;68(9):4623–8.
3. Asiedu K, Etuaful S. Socioeconomic implications of Buruli ulcer in Ghana: a three-year review. Am J Trop Med Hyg 1998;59(6):1015–22. 4. Demangel C, Stinear TP, Cole ST. Buruli ulcer: reductive evolution enhances pathogenicity of Mycobacterium ulcerans. Nat Rev Microbiol 2009;7(1):50. 5. Schütte D, Um-Boock A, Mensah-Quainoo E, et al. Development of highly organized lymphoid structures in Buruli ulcer lesions after treatment with rifampicin and streptomycin. PLoS Negl Trop Dis 2007;1(1):e2. 6. Phillips R, Sarfo F, Osei-Sarpong F, et al. Sensitivity of PCR targeting Mycobacterium ulcerans by use of fine-needle aspirates for diagnosis of Buruli ulcer. J Clin Microbiol 2009;47(4):924–6. 7. Chauty A, Ardant M-F, 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. 8. Nienhuis WA, Stienstra Y, Thompson WA, et al. Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet 2010;375(9715):664–72.
63
Buruli Ulcer Mark H. Wansbrough-Jones, Richard O. Phillips
KEY FEATURES • Mycobacterium ulcerans causes chronic skin ulcers, referred to as Buruli ulcers. • Common in parts of rural West Africa, but the mode of transmission is unknown. • Subcutaneous necrosis is caused by secretion of mycolactone toxin, a plasmid-encoded polyketide molecule. • Diagnosis is usually based on clinical recognition; polymerase chain reaction (PCR)–based analysis is also used. • Treatment includes 8 weeks of rifampin and clarithromycin. • Early recognition and treatment, including physiotherapy, can prevent disabilities.
INTRODUCTION Buruli ulcer is a neglected tropical disease caused by skin infection with Mycobacterium ulcerans. It is of considerable importance in rural parts of West and Central Africa, where it affects children and young adults and causes an economic burden on farming communities. Extensive ulceration is caused by a lipid toxin called mycolactone secreted by M. ulcerans, a pathogenesis not seen with other mycobacteria.
EPIDEMIOLOGY AND TRANSMISSION Buruli ulcer is a disease of high focal prevalence mainly within countries in West Africa (Fig. 63.1), but sporadic cases have been reported in many countries with high humidity in tropical wetlands. Buruli ulcer has been seen among people living in more than 30 countries around the world (Fig. 63.2), including French Guiana, Peru, Mexico, Papua New Guinea, Japan, and southern China. Outbreaks are also observed in temperate south eastern Australia, where the association of M. ulcerans with Buruli (Bairnsdale) ulcer was first recognized in 1948. Disturbance of water systems by mining, deforestation, or flooding has been associated with increased incidence of disease. Newly arrived migrants in endemic zones are susceptible to infection, as demonstrated by the occurrence of Buruli ulcer among displaced Rwandans in the Kinyara refugee camps in Uganda in the 1960s. These refugees had come from a non-endemic zone and developed ulcers within 4 to 10 weeks of arrival, suggesting the disease’s incubation period. M. ulcerans has been identified in skin lesions of wild koalas and ringtail possums in Australia and of mice in West Africa. It is difficult to culture, although it has been isolated from fresh water bugs in endemic zones after serial passage in mice.1 M. ulcerans probably exists in an ecologic niche related to slowflowing or stagnant water in West Africa, but how it is transmitted to humans remains unknown. Experimental evidence shows that it can be transmitted from infected water bugs to mice by biting.2 In Australia, DNA from M. ulcerans was detected in mosquitoes
from an affected area but not in mosquitoes from a non-infected area, as well as in possum feces; however, the significance of these observations is unclear. Buruli ulcer can affect people of all ages, but in West Africa it predominantly affects children aged 5 to 15 years, and in southeast Australia, it affects elderly residents in retirement towns.
CLINICAL PRESENTATION Most patients with Buruli ulcer present with a chronic ulcer, often of a few months’ duration. Patients fail to present early because the lesions are painless, and affected individuals often live in remote rural areas lacking easy access to affordable health care.3 The disease manifests as a 1- to 5-cm, painless, subcutaneous nodule attached to the overlying skin (Fig. 63.3A). In Australia, early lesions are often papular. More extensive indurated plaques may also occur, the margins of which are difficult to define. Nodules, plaques, and ulcers may be associated with edema in surrounding tissue (10%–15% in Ghana), which spreads outwards (Fig. 63.3B). Ulceration spreads from the initial lesion into edematous areas. The patient remains well, and there is no fever or pain unless secondary bacterial infection occurs. Occasionally, osteomyelitis occurs in bone adjacent to a skin lesion, but involvement of other organs is rare. The distinguishing features of Buruli ulcers are that they are painless and that the edges are undermined so that a swab can be pushed a few millimeters (or sometimes centimeters) under the surrounding skin (Fig. 63.3C). The ulcer border is not raised. Tissue destruction is caused by cytotoxic mycolactone toxin that also prevents the development of an inflammatory response.4 The process is chronic, and histologic examination of affected tissue often shows a mixture of scar formation; featureless necrosis around clumps of proliferating acid-fast mycobacteria; and acute, chronic, and granulomatous inflammation. Organisms are rarely seen within macrophages in untreated lesions, but careful immunohistologic studies have demonstrated that intracellular organisms can be observed during antibiotic treatment when the effect of mycolactone is lost.5 In 90% of cases, ulcers involve the limbs, but they can also involve the head, neck, or trunk. When scarring occurs close to a joint, there is often limitation of joint movement; large lesions on the trunk may inhibit spinal movement. Buruli ulcers recognize no anatomic boundaries and may involve critical sites, such as the face, breast, and genital area.
DIAGNOSIS Diagnosis is usually based on clinical recognition. Buruli ulcers on the lower extremities may be difficult to distinguish from diabetic or venous stasis ulcers. Acid-fast bacilli can be detected in about 40% of ulcers when a swab is taken from the base, close to undermined areas. Cultures (on Löwenstein–Jensen medium at 32°C) are more sensitive (up to 60% positive), yielding mycobacterial growth when performed in a laboratory near the endemic area, but it can take 6 weeks or more for mycobacterial growth to be detectable. Histologic examination can be 85% sensitive but is not available in many endemic areas. The most sensitive diagnostic test (98%) is polymerase chain reaction (PCR) for the
565
566
PART 3 Bacterial Infections
Fig. 63.1 Buruli ulcer incidence in Ghana during 2008. (Map created by Julie Clennon, Rollins School of Public Health, from data provided by Edwin Ampadu and William Opare, Ghana National BU Control Programme. Funded by National Institute of Environmental Health Sciences grants #R01ES015525 and #T32ES012160.)
Number of reported cases, 2016 ≥500
No cases reported
300–499
Previously reported cases
100–299
Not applicable
<100 Fig. 63.2 New cases of Buruli ulcer reported to the WHO in 2016. (Provided by Dr. Kingsley Asiedu, WHO.)
CHAPTER 63 Buruli Ulcer
567
63
A
B
C Fig. 63.3 Clinical forms of Buruli ulcer disease. (A) Subcutaneous, firm, painless nodule attached to the skin. (B) Extensive edema of the left arm and leg and genitalia with ulceration on the left arm and knee. (C) Partially debrided ulcer on the right knee with further ulceration on the leg and foot. All the ulcers were probably connected subcutaneously.
IS2404 repeat sequence of M. ulcerans. PCR can be applied to swabs, punch biopsies (3–4 mm diameter), and fine needle aspirates. The latter approaches may be helpful in diagnosing individual nodules, plaques, and edematous lesions that have not yet ulcerated.6
release up to a maximum of 500 mg orally twice a day for 8 weeks. Fluoroquinolone antibiotics also have some activity. The standard dressing is gauze coated with Vaseline which is changed daily. Most lesions heal without surgical intervention, but occasionally debridement and split-skin grafting are needed for large ulcers.
MANAGEMENT
COMPLICATIONS
Daily treatment under observation with rifampin 10 mg/kg (up to 600 mg per day) orally and streptomycin 15 mg/kg intramuscularly for 8 weeks results in healing of all forms of M. ulcerans disease with few exceptions.7 Recurrence after antibiotic treatment is rare (0%–2.5%). A controlled trial has shown that clarithromycin can be substituted for streptomycin in the second 4 weeks of treatment without loss of efficacy,8 and recently a controlled trial comparing rifampin plus clarithromycin for 8 weeks with rifampin plus streptomycin for 8 weeks has been completed. Preliminary results show equivalent results for the fully oral regimen, and because streptomycin is no longer available routinely, the World Health Organization (WHO) expert advisors have now recommended rifampin 10 mg/kg (up to maximum 600 mg daily) orally combined with clarithromycin 15 mg/kg orally daily if extended release preparation, or divided into two doses if not extended
Chronic ulceration leads to disfiguring scars and significant loss of tissue. Extensive ulcers on the limbs sometimes require amputation, particularly when there is concurrent osteomyelitis. Secondary bacterial infection of a Buruli ulcer may cause life-threatening septicemia. Paradoxical reactions, characterized by increased inflammation and lesion size or the appearance of new lesions, occur in up to 10% of patients. A fluctuant mass may appear close to the initial lesion during antibiotic treatment, and purulent discharge that is usually sterile can be aspirated. These lesions resolve without additional antibiotic treatment. When a Buruli ulcer is close to a joint, there may be limitation of joint movement and an increased risk of scarring. Functional limitation can be prevented by simple physiotherapy that can be taught to the patient and family when treatment is started.
568
PART 3 Bacterial Infections
PREVENTION Understanding how M. ulcerans infection is transmitted to humans is a priority, as this information could lead to preventive strategies. Epidemiologic studies have shown that exposure to water sources near endemic villages is a risk factor for developing Buruli ulcer, but reducing exposure, particularly of children, to such sources is impractical in rural West Africa. No effective vaccine is currently available, although Bacillus Calmette–Guérin (BCG) vaccine has been associated with shortlived protection in small trials. Outreach programs to educate communities in endemic areas to recognize early Buruli lesions is vital for prevention of severe forms of the disease. REFERENCES
1. 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. 2. Marsollier L, Robert R, Aubry J, et al. Aquatic insects as a vector for Mycobacterium ulcerans. Appl Environ Microbiol 2002;68(9):4623–8.
3. Asiedu K, Etuaful S. Socioeconomic implications of Buruli ulcer in Ghana: a three-year review. Am J Trop Med Hyg 1998;59(6):1015–22. 4. Demangel C, Stinear TP, Cole ST. Buruli ulcer: reductive evolution enhances pathogenicity of Mycobacterium ulcerans. Nat Rev Microbiol 2009;7(1):50. 5. Schütte D, Um-Boock A, Mensah-Quainoo E, et al. Development of highly organized lymphoid structures in Buruli ulcer lesions after treatment with rifampicin and streptomycin. PLoS Negl Trop Dis 2007;1(1):e2. 6. Phillips R, Sarfo F, Osei-Sarpong F, et al. Sensitivity of PCR targeting Mycobacterium ulcerans by use of fine-needle aspirates for diagnosis of Buruli ulcer. J Clin Microbiol 2009;47(4):924–6. 7. Chauty A, Ardant M-F, 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. 8. Nienhuis WA, Stienstra Y, Thompson WA, et al. Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet 2010;375(9715):664–72.