Kingsley Asiedu

Mycobacterium ulcerans infection

After tuberculosis and leprosy, Buruli-ulcer disease (caused by infection with Mycobacterium ulcerans) is the third most common mycobacterial disease in immunocompetent people. Countries in which the disease is endemic have been identified, predominantly in areas of tropical rain forest; the emergence of Buruli-ulcer disease in West African countries over the past decade has been dramatic. Current evidence suggests that the infection is transmitted through abraded skin or mild traumatic injuries after contact with contaminated water, soil, or vegetation; there is one unconfirmed preliminary report on possible transmission by insects. The clinical picture ranges from a painless nodule to large, undermined ulcerative lesions that heal spontaneously but slowly. Most patients are children. The disease is accompanied by remarkably few systemic symptoms, but occasionally secondary infections resulting in sepsis or tetanus cause severe systemic disease and death. Extensive scarring can lead to contractures of the limbs, blindness, and other adverse sequelae, which impose a substantial health and economic burden. Treatment is still primarily surgical, and includes excision, skin grafting, or both. Although BCG has a mild but significant protective effect, new vaccine developments directed at the toxins produced by M. ulcerans are warranted. In West Africa, affected populations are underprivileged, and the economic burden imposed by Buruli-ulcer disease is daunting. Combined efforts to improve treatment, prevention, control, and research strategies (overseen by the WHO and funded by international relief agencies) are urgently needed.

Efficacy of the combination rifampin-streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans

ABSTRACT Mycobacterium ulcerans disease is common in some humid tropical areas, particularly in parts of West Africa, and current management is by surgical excision of skin lesions ranging from early nodules to extensive ulcers (Buruli ulcer). Antibiotic therapy would be more accessible to patients in areas of Buruli ulcer endemicity. We report a study of the efficacy of antibiotics in converting early lesions (nodules and plaques) from culture positive to culture negative. Lesions were excised either immediately or after treatment with rifampin orally at 10 mg/kg of body weight and streptomycin intramuscularly at 15 mg/kg of body weight daily for 2, 4, 8, or 12 weeks and examined by quantitative bacterial culture, PCR, and histopathology for M. ulcerans. Lesions were measured during treatment. Five lesions excised without antibiotic treatment and five lesions treated with antibiotics for 2 weeks were culture positive, whereas three lesions treated for 4 weeks, five treated for 8 weeks, and three treated for 12 weeks were culture negative. No lesions became enlarged during antibiotic treatment, and most became smaller. Treatment with rifampin and streptomycin for 4 weeks or more inhibited growth of M. ulcerans in human tissue, and it provides a basis for proceeding to a trial of antibiotic therapy as an alternative to surgery for early M. ulcerans disease.

Buruli ulcer in Ghana: results of a national case search.

A national search for cases of Buruli ulcer in Ghana identified 5,619 patients, with 6,332 clinical lesions at various stages. The overall crude national prevalence rate of active lesions was 20.7 per 100,000, but the rate was 150.8 per 100,000 in the most disease-endemic district. The case search demonstrated widespread disease and gross underreporting compared with the routine reporting system. The epidemiologic information gathered will contribute to the design of control programs for Buruli ulcer.

Buruli Ulcer (M. ulcerans Infection): New Insights, New Hope for Disease Control

Buruli ulcer is a disease of skin and soft tissue caused by Mycobacterium ulcerans. It can leave affected people scarred and disabled. What are the prospects for disease control?

Mycobacterium ulcerans disease

Mycobacterium ulcerans disease (Buruli ulcer) is an important health problem in several west African countries. It is prevalent in scattered foci around the world, predominantly in riverine areas with a humid, hot climate. We review the epidemiology, bacteriology, transmission, immunology, pathology, diagnosis and treatment of infections. M. ulcerans is an ubiquitous micro-organism and is harboured by fish, snails, and water insects. The mode of transmission is unknown. Lesions are most common on exposed parts of the body, particularly on the limbs. Spontaneous healing may occur. Many patients in endemic areas present late with advanced, severe lesions. BCG vaccination yields a limited, relatively short-lived, immune protection. Recommended treatment consists of surgical debridement, followed by skin grafting if necessary. Many patients have functional limitations after healing. Better understanding of disease transmission and pathogenesis is needed for improved control and prevention of Buruli ulcer.

Clinical efficacy of combination of rifampin and streptomycin for treatment of Mycobacterium ulcerans disease.

ABSTRACT We have evaluated the clinical efficacy of the combination of oral rifampin at 10 mg/kg of body weight and intramuscular streptomycin at 15 mg/kg for 8 weeks (RS8), as recommended by the WHO, in 160 PCR-confirmed cases of Mycobacterium ulcerans disease. In 152 patients (95%) with all forms of disease from early nodules to large ulcers, with or without edema, the lesions healed without recourse to surgery. Eight patients whose ulcers were healing poorly had skin grafting after completion of antibiotics. There were no recurrences among 158 patients reviewed at the 1-year follow-up. The times to complete healing ranged from 2 to 48 weeks, according to the type and size of the lesion, but the average rate of healing (rate of reduction in ulcer diameter) varied widely. Thirteen subjects had positive cultures for M. ulcerans during or after treatment, but all the lesions healed without further antibiotic treatment. Adverse events were rare. These results confirm the efficacy of RS8 delivered in a community setting.

Mass treatment with single-dose azithromycin for yaws

BACKGROUND Mass treatment with azithromycin is a central component of the new World Health Organization (WHO) strategy to eradicate yaws. Empirical data on the effectiveness of the strategy are required as a prerequisite for worldwide implementation of the plan. METHODS We performed repeated clinical surveys for active yaws, serologic surveys for latent yaws, and molecular analyses to determine the cause of skin ulcers and identify macrolide-resistant mutations before and 6 and 12 months after mass treatment with azithromycin on a Papua New Guinean island on which yaws was endemic. Primary-outcome indicators were the prevalence of serologically confirmed active infectious yaws in the entire population and the prevalence of latent yaws with high-titer seroreactivity in a subgroup of children 1 to 15 years of age. RESULTS At baseline, 13,302 of 16,092 residents (82.7%) received one oral dose of azithromycin. The prevalence of active infectious yaws was reduced from 2.4% before mass treatment to 0.3% at 12 months (difference, 2.1 percentage points; P<0.001). The prevalence of high-titer latent yaws among children was reduced from 18.3% to 6.5% (difference, 11.8 percentage points; P<0.001) with a near-absence of high-titer seroreactivity in children 1 to 5 years of age. Adverse events identified within 1 week after administration of the medication occurred in approximately 17% of the participants, included nausea, diarrhea, and vomiting, and were mild in severity. No evidence of emergence of resistance to macrolides against Treponema pallidum subspecies pertenue was seen. CONCLUSIONS The prevalence of active and latent yaws infection fell rapidly and substantially 12 months after high-coverage mass treatment with azithromycin, with the reduction perhaps aided by subsequent activities to identify and treat new cases of yaws. Our results support the WHO strategy for the eradication of yaws. (Funded by Newcrest Mining and International SOS; YESA-13 ClinicalTrials.gov number, NCT01955252.).

Sensitivity of PCR Targeting Mycobacterium ulcerans by Use of Fine-Needle Aspirates for Diagnosis of Buruli Ulcer

ABSTRACT In a previous study, we reported that the sensitivity of PCR targeting the IS2404 insertion sequence of Mycobacterium ulcerans was 98% when it was applied to 4-mm punch biopsy samples of Buruli lesions. Fine-needle aspiration (FNA) is a less traumatic sampling technique for nonulcerated lesions, and we have studied the sensitivity of PCR using FNA samples. Fine-needle aspirates were taken with a 21-gauge needle from 43 patients diagnosed clinically with M. ulcerans disease. Four-millimeter punch biopsies were obtained for microscopy, culture, and PCR targeting the IS2404 insertion sequence. The sensitivity of PCR using samples obtained by FNA was 86% (95% confidence interval [95% CI], 72 to 94%) compared with that for PCR using punch biopsy samples. In this study, the sensitivities of culture and microscopy for punch biopsy samples were 44% (95% CI, 29 to 60%) and 26% (95% CI, 14 to 41%), respectively. This demonstrates that PCR on an FNA sample is a viable minimally invasive technique to diagnose M. ulcerans lesions.

Yaws Eradication: Past Efforts and Future Perspectives

Yaws, a disease primarily affecting skin, bones and cartilage, is caused by Treponema pallidum subspecies pertenue. Together with bejel (endemic syphilis) and pinta, these diseases constitute the group of the endemic treponematoses.1 If left untreated, yaws leads to crippling and disfiguring consequences.2 Between 1952 and 1964, WHO and the United Nations Children’s Fund (UNICEF) led a worldwide campaign to control and eventually eradicate yaws and other endemic treponematoses.3 This was a major disease control effort undertaken by WHO just after its establishment in 1948.4 Control programmes were established in 46 countries and, by the end of 1964, the number of cases had been reduced from 50 million to 2.5 million (a 95% reduction).5 The yaws control efforts paved the way for the development of the primary health care system in affected areas.6 In the late 1960s, there was a shift in strategy from the vertical programme to integration of yaws surveillance and control into primary health care to tackle the remaining 5% of cases. However, this approach did not succeed. By the end of the 1970s, re-emergence of yaws in many countries prompted a World Health Assembly Resolution requesting the implementation of integrated treponematoses control programmes.7 Renewed control efforts were implemented in several countries, e.g. Benin, Burkina Faso, Cote d’Ivoire, Ghana, Mali, the Niger and Togo, but these efforts were not sustained. In 1984, a global meeting was organized in Washington, DC,8 followed by regional meetings with the aim of reviving eradication activities. These attempts were half-hearted and the goal of eradication remained elusive.9 At this time, most of the yaws programmes had been integrated into primary health care which were generally too weak to implement the activities of a vertical programme.10 In 1995, WHO estimated the number of infectious cases to be 460 000 worldwide of which, 400 000 were in west and central Africa, 50 000 in South-East Asia and the rest in other tropical regions.11 The South-East Asia Region of WHO kept yaws high on its agenda and set the goal of regional eradication by 2012 in its two remaining endemic countries – Indonesia and Timor-Leste. Since 2004, India has reported no new cases.12 In the Western Pacific Region, three countries remain endemic – Papua New Guinea, the Solomon Islands and Vanuatu. The main lessons learned from the past are that yaws can be eliminated with sustained efforts as shown in many countries and recently in India; however, success can also lead to complacency and neglect. Once the goal and timeframe are set, political will and donor commitment need to be sustained until transmission is interrupted. Health services with adequate outreach activities to remote communities are pivotal for effective disease control efforts. The elimination of a disease from one geographical area is not a guarantee against its re-introduction. But all is not lost: benzathine penicillin is still very effective, safe, cheap and readily available. It offers a remarkable cure in a single injection which reinforces high community confidence and participation in yaws activities. Today, the favourable environment for neglected tropical diseases may help with visibility and mobilization of resources to tackle yaws, and it provides the possibility to integrate yaws activities into other programmes. Additional opportunities and resources for health system strengthening, global health initiatives and renewed interest in primary health care may further facilitate elimination efforts. However, challenges in reviving yaws control remain. The disease is no longer perceived as a priority by national health policy-makers. Furthermore, knowledge and skills of health workers to diagnose and manage yaws have waned. Accessibility to affected populations in remote areas is a challenge. Finally, the risk of penicillin resistance remains,13 hence alternative antibiotics should be explored. In retrospect, the world should have dealt a final blow to yaws in the late 1960s and the 1970s. Today’s favourable environment in health and development provides an opportunity to revive elimination efforts. Presently, the problem of yaws is relatively small; justification for action should not only be based on number of cases but also on humanitarian grounds as the disease affects poor and underserved populations. The International Task Force on Disease Eradication strongly recommended that WHO and UNICEF take the lead in addressing this highly curable and preventable neglected tropical disease.14 The 60th anniversary of WHO is an opportunity for governments of the remaining endemic countries and the international community to reflect on the continued existence of yaws and to encourage and support renewed efforts to eliminate the disease. ■

The return of yaws.

Yaws, a disease primarily affecting skin, bones and cartilage, is caused by Treponema pallidum subspecies pertenue. Together with bejel (endemic syphilis) and pinta, these diseases constitute the group of the endemic treponematoses.1 If left untreated, yaws leads to crippling and disfiguring consequences.2 Between 1952 and 1964, WHO and the United Nations Children’s Fund (UNICEF) led a worldwide campaign to control and eventually eradicate yaws and other endemic treponematoses.3 This was a major disease control effort undertaken by WHO just after its establishment in 1948.4 Control programmes were established in 46 countries and, by the end of 1964, the number of cases had been reduced from 50 million to 2.5 million (a 95% reduction).5 The yaws control efforts paved the way for the development of the primary health care system in affected areas.6 In the late 1960s, there was a shift in strategy from the vertical programme to integration of yaws surveillance and control into primary health care to tackle the remaining 5% of cases. However, this approach did not succeed. By the end of the 1970s, re-emergence of yaws in many countries prompted a World Health Assembly Resolution requesting the implementation of integrated treponematoses control programmes.7 Renewed control efforts were implemented in several countries, e.g. Benin, Burkina Faso, Cote d’Ivoire, Ghana, Mali, the Niger and Togo, but these efforts were not sustained. In 1984, a global meeting was organized in Washington, DC,8 followed by regional meetings with the aim of reviving eradication activities. These attempts were half-hearted and the goal of eradication remained elusive.9 At this time, most of the yaws programmes had been integrated into primary health care which were generally too weak to implement the activities of a vertical programme.10 In 1995, WHO estimated the number of infectious cases to be 460 000 worldwide of which, 400 000 were in west and central Africa, 50 000 in South-East Asia and the rest in other tropical regions.11 The South-East Asia Region of WHO kept yaws high on its agenda and set the goal of regional eradication by 2012 in its two remaining endemic countries – Indonesia and Timor-Leste. Since 2004, India has reported no new cases.12 In the Western Pacific Region, three countries remain endemic – Papua New Guinea, the Solomon Islands and Vanuatu. The main lessons learned from the past are that yaws can be eliminated with sustained efforts as shown in many countries and recently in India; however, success can also lead to complacency and neglect. Once the goal and timeframe are set, political will and donor commitment need to be sustained until transmission is interrupted. Health services with adequate outreach activities to remote communities are pivotal for effective disease control efforts. The elimination of a disease from one geographical area is not a guarantee against its re-introduction. But all is not lost: benzathine penicillin is still very effective, safe, cheap and readily available. It offers a remarkable cure in a single injection which reinforces high community confidence and participation in yaws activities. Today, the favourable environment for neglected tropical diseases may help with visibility and mobilization of resources to tackle yaws, and it provides the possibility to integrate yaws activities into other programmes. Additional opportunities and resources for health system strengthening, global health initiatives and renewed interest in primary health care may further facilitate elimination efforts. However, challenges in reviving yaws control remain. The disease is no longer perceived as a priority by national health policy-makers. Furthermore, knowledge and skills of health workers to diagnose and manage yaws have waned. Accessibility to affected populations in remote areas is a challenge. Finally, the risk of penicillin resistance remains,13 hence alternative antibiotics should be explored. In retrospect, the world should have dealt a final blow to yaws in the late 1960s and the 1970s. Today’s favourable environment in health and development provides an opportunity to revive elimination efforts. Presently, the problem of yaws is relatively small; justification for action should not only be based on number of cases but also on humanitarian grounds as the disease affects poor and underserved populations. The International Task Force on Disease Eradication strongly recommended that WHO and UNICEF take the lead in addressing this highly curable and preventable neglected tropical disease.14 The 60th anniversary of WHO is an opportunity for governments of the remaining endemic countries and the international community to reflect on the continued existence of yaws and to encourage and support renewed efforts to eliminate the disease. ■