Theoretical Assessment of Environmental Factors and Untreated Infectious Individuals in the Transmission Dynamics of Buruli ulcer

Buruli ulcer is the third most common mycobacterial disease worldwide, posing a significant public health burden, especially in impoverished regions of West and Central Africa, such as Benin. The management of Buruli ulcer (BU) in Africa is often hindered by limited resources, delays in treatment, and inadequate medical facilities. Additionally, a portion of the population does not seek hospital care, which facilitates the continued presence of the pathogen in the environment. This paper aims to investigate the role of environmental factors in the transmission of Buruli ulcer. We develop a mathematical model to describe the dynamics of Buruli ulcer transmission, incorporating the presence of the bacterium in the environment. Theoretical results are presented to demonstrate that the model is well-posed. We compute the equilibria, including the disease-free equilibrium and the endemic equilibrium, and study their stability. To achieve this, we derive a threshold parameter called the basic reproduction number ℛ0, which determines whether the disease will persist in a human population. If ℛ0is less than one, the disease will eventually die out;if ℛ0is greater than one, the disease will persist. Sensitivity analysis is performed to understand the impact of various parameters on the dynamics of Buruli ulcer transmission and to identify the parameters that influence the basic reproduction number ℛ0. Finally, numerical simulations are conducted to validate the theoretical results obtained from the mathematical analysis.

Assessment of the 2 Conventional Physiotherapy Sessions Alone versus One Session Associated to Kabat’s Method in the Rehabilitation of Buruli Ulcer Patients (PUB), with Functional Limitations in the District Hospital of Akonolinga, Cameroon

Buruli ulcer (BU) is a chronic, indolent necrotizing disease of the skin and underlying tissues caused by Mycobacterium ulcerans, which may result in functional disability. This disease is the third most frequent infection after leprosy and tuberculosis caused by a mycobacterium. The main objective of this study was to determine comparative effectiveness of conventional physiotherapy alone to its association with Kabat’s method in the management of post-Buruli ulcer functional limitations. This was an interventional randomized, comparative and prospective study. It took place at the district hospital of Akonolinga from the 12th June to 12th September 2016. The study was included, post-Buruli ulcer patients who matched the eligibility criteria, were under treatment in the physiotherapy unit, and who accepted to participate in our study. A questionnaire on the socio-demographic profile of participants, the ulcer localization, the limitation stage, previous medical history and functional mobility assessment scale was administered to the subjects before and after the intervention which lasted for twelve weeks. We had 2 groups: the case group received association of Kabat technique to conventional physiotherapy and the control group received conventional physiotherapy alone. We had 22 patients, 11 patients for the experimental group, 11 patients for the control group. The mean age was 26.18 years, 54.5% of female participation, 68.2% of leg localization, 59.1% patients with severe limitations of functional mobility, and preference for traditional medication 95.5%. After evaluation of efficiency, we concluded that there was no statistically significant difference between the two treatment protocols. Further studies with larger sample size are recommended.

Buruli Ulcer and HIV Coinfection: Cases in Togo

Background: In Togo, as in all sub-Saharan countries, the burden of HIV infection remains high. The registration of new cases of Buruli ulcer every year also remains a major public health problem. Buruli ulcer (BU) is a disabling disease and the presentation of lesions is frequently severe. A feature of BU and HIV coinfection is the rarity of cases, which makes its study difficult, but, nevertheless, important to study its seroprevalence, biological data, risk factors and genetic diversity. The purpose of this study is to explore the comorbidity of Buruli ulcer and HIV by evaluating HIV seroprevalence in BU patients, assessing demographic data, reviewing biological data including CD4+ T cell count, hemoglobin levels, and viral loads, and evaluating clinical and therapeutic data. Methods: This is a cross-sectional study including only BU patients confirmed by Ziehl Neelsen staining and IS 2404 PCR. The patients were hospitalized in the National Reference Center for Tsevie. They were recovered patients and patients undergoing outpatient treatment in the Gati and Tchekpo Deve treatment centers, respectively, within the Sanitary Districts of Zio and Yoto of the Maritime Region during the period from August 2015 to March 2017. Results: The number of HIV-positive BU patients is 4 out of a total of 83 BU patients. All patients are HIV-1 positive. HIV prevalence among BU patients is 4.8% compared to 2.5% nationally and 3% at regional level. Three BU patients are seropositive out of a total of 46 female patients while one patient under 15 years is seropositive out of a total of 37 male BU patients. There are a greater proportion of female patients with BU/HIV coinfections. Half of the BU/HIV positive patients (BU/HIV+) have a CD4+ TL of fewer than 500 cells/μl and the difference is significant between those of the BU HIV- and those of the BU/HIV+ patients. Two patients have undetectable viral loads while the other two have more than 1000 copies/ml (33,000 and 1,100,000 copies/ml). Anemia is significantly present in BU/HIV+ patients with a p-value = 0.003. Half of BU patients have primary education, while three-quarters of BU/HIV+ patients have no education. All patients are either in stage I or stage II of the AIDS WHO classification. All patients are on first line ARV therapy and only ARV nucleoside reverse transcriptase inhibitors (NRTIs) are used. Conclusion: In Togo, the prevalence of HIV in BU patients, although higher, is not significantly different from that of national and regional. The relatively high CD4+ LT levels of relatively high BU HIV + patients, undetectable viral loads, and AIDS WHO stages I and II indicate good quality management. Author Summary: Buruli ulcer disease (BUD) is a mycobacterial skin disease that leads to extensive ulcerations and causes disabilities in approximately 25% of the patients. Co-infection with HIV is described by the authors through the prism of risk factors and the severity of ulcerations. Healing time is described as longer than in BU/HIV- patients. The scarcity of cases seems to be an obstacle for further study. Noteworthy are the study of cases in Benin and the study of cohort cases in Cameroon. However, no study appears to be based on the seroprevalence of this morbid association, the biological data and the antiretroviral regimens. These regimens, if poorly instituted, conflict with antimycobacterial drugs against Buruli ulcer. This study, although confronted with the particular configuration of Togo, a country with a low HIV prevalence of 2.8% national prevalence and an average of 55 cases of Buruli ulcer per year, is studying the biological aspects of co-infection HIV/BU, including seroprevalence of HIV, CD4+ LT levels, patient viral load and hemoglobin levels and ARV regimens. This study shows the need for future studies, including the study of the genetic diversity of circulating Mycobacterium ulcerans strains in Togo and the study of Buruli ulcer co-infection/HIV and tuberculosis.

<i>In Vivo</i>Evaluation of Anti-Mycobacterial Activity of a Phytomedicine “MATHESIA” on <i>Mycobacterium ulcerans</i>: Influence of Alkalinity on the Activity of Antibiotics Used in the Treatment of Buruli Ulcer

The present study reports the in vivo anti-Mycobacterial Activity of a Phytomedicine “MATHESIA” on Mycobacterium ulcerans. It also explores the influence of ethanolamine (alkali agent) on the in vivo activity of some antibiotics (Isoniazid, Rifampicin, Ethambutol) used in the treatment of Buruli ulcers in DR Congo. Experiments were conducted on adult white Wistar rats of both sexes with the weights comprising between 110 - 165 g. The result obtained have shown that the phytomedicine MATHESIA (pH 10) has a good in vivo activity on M. ulcerans and the duration for wounds healing and total cicatrization was 6 days;whereas this duration was 10, 12, 14, and 16 days respectively for Rifampicin (IV, pH 10), Kibadi’s solution (X, pH 10), Ethambutol (VIII, pH 10) and Isoniazid (VI, pH 10). The result also showed that the use of the ethanolamine as alkali compounded in the treatment of wounds due to Buruli ulcer along with other antibiotics reduced considerably the duration of complete healing comparatively to their solutions at pH bellow or equal to 7.

Buruli Ulcer: Epidemiological, Clinical and Biological Profile of Patients in the Centre de Depistage et de Traitement d’Allada (Benin) from 2010 to 2014

Introduction: The objective of our work was to describe the epidemiological, clinical and biological profile of Buruli ulcer in “Centre de Dépistage et de traitement de l’ulcère de Buruli” (CDTUB) in Allada. Methods: A descriptive and retrospective study focused on new cases of Buruli ulcer received in the CDTUB of Allada from 2010 to 2014. The diagnosis of Buruli ulcer was based on epidemiological, clinical and biological arguments. Results: Over 5 years, 274 new cases of Buruli ulcer have been diagnosed. The average age of the patients was 12 years and the sex ratio was 0.8. The average time to first consultation was 45 days. Clinically, 61% had a joint functional limitation. Lesions were ulcerated in 69% of cases, category I (26%), category II (53%), category III (21%) and were present on the lower limbs in 57% of cases. Microscopy was positive in 65.7% of cases and PCR in 78.1% of cases. Microscopy supplemented by PCR confirmed the diagnosis in 81% of cases. Conclusion: The epidemiological, clinical and biological profile of Buruli ulcer in Allada was characterized by a predominant disease in children, a predominance of ulcerated forms and a decisive contribution of PCR to the diagnosis.

Mental health and quality of life burden in Buruli ulcer disease patients in Ghana

Background Buruli ulcer disease(BUD)is a necrotic skin neglected tropical disease(NTD)that has both a mental and physical health impact on affected individuals.Although there is increasing evidence suggesting a strong association between neglected tropical diseases(NTDs)and mental illness,there is a relative lack of information on BUD’s impact on the mental health and quality of life(QoL)of affected individuals in Ghana.This study is to assess the impact of BUD on mental health and quality of life of patients with active and past BUD infection,and their caregivers.Methods We conducted a case control study in 3 BUD endemic districts in Ghana between August and November 2019.Face-to-face structured questionnaire-based interviews were conducted on BUD patients with active and past infection,as well as caregivers of BUD patients using WHO Quality of Life scale,WHO Disability Assessment Schedule,Self-Reporting Questionnaire,Buruli Ulcer Functional Limitation Score and Hospital Anxiety and Depression Scale data tools.Descriptive statistics were used to summarize the characteristics of the study participants.Participant groups were compared using student t test and chi-square(χ2)or Fisher’s exact tests.Mean quality of life scores are reported with their respective 95%confidence intervals.Data was analysed using STATA statistical software.Results Our results show that BUD patients with active and past infection,along with their caregivers,face significant levels of distress and mental health sequelae compared to controls.Depression(P=0.003)was more common in participants with active(27%)and past BU infection(17%),compared to controls(0%).Anxiety was found in 42%(11/26)and 20%(6/29)of participants with active and past BUD infection compared to 14%(5/36)of controls.Quality of life was also significantly diminished in active BUD infection,compared to controls.In the physical health domain,mean QoL scores were 54±11.1 and 56±11.0(95%CI:49.5‒58.5 and 52.2‒59.7)respectively for participants with active infection and controls.Similarly in the psychological domain,scores were lower for active infection than controls[57.1±15.2(95%CI:50.9‒63.2)vs 64.7±11.6(95%CI:60.8‒68.6)].Participants with past infection had high QoL scores in both physical[61.3±13.5(95%CI:56.1‒66.5)]and psychological health domains[68.4±14.6(95%CI:62.7‒74.0)].Conclusions BUD is associated with significant mental health distress and reduced quality of life in affected persons and their caregivers in Ghana.There is a need for integration of psychosocial interventions in the management of the disease.

Modeling the transmission of Buruli ulcer in fluctuating environments

The transmission dynamics of Buruli ulcer （BU） largely depends on environmental changes. In this paper a deterministic model for the transmission of BU in fluctuating environments is proposed. The model incorporates periodicity in the disease transmission pathways and the Mycobacterium ulcerans density that are thought to vary seasonally. Two reproduction numbers, the time-averaged reproduction number [R0l and the basic reproduction number R0, are determined and compared. It is shown that the time-averaged reproduction underestimates the number of infections. Numerical simulations confirmed that if R0 〉 1 the infection is sustained seasonally. The model outcome suggests that environmental fluctuations should be taken into consideration in designing policies aimed at BU control and management.

Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans

Buruli ulcer(BU),caused by Mycobacterium ulcerans,is currently treated with rifampin estreptomycin or rifampineclarithromycin daily for 8 weeks recommended by World Health Organization(WHO).These options are lengthy with severe side effects.A new anti-tuberculosis drug,TB47,targeting QcrB in cytochrome bc1:aa3 complex is being developed in China.TB47-containing regimens were evaluated in a well-established murine model using an autoluminescent M.ulcerans strain.Highlevel TB47-resistant spontaneous M.ulcerans mutants were selected and their qcrB genes were sequenced.The in vivo activities of TB47 against both low-level and high-level TB47-resistant mutants were tested in BU murine model.Here,we show that TB47-containing oral 3-drug regimens can completely cure BU in 2 weeks for daily use or in 3 weeks given twice per week(6 doses in total).All high-level TB47-resistant mutants could only be selected using the low-level mutants which were still sensitive to TB47 in mice.This is the first report of double mutations in QcrB in mycobacteria.In summary,TB47-containing regimens have promise to cure BU highly effectively and prevent the emergence of drug resistance.Novel QcrB mutations found here may guide the potential clinical molecular diagnosis of resistance and the discovery of new drugs against the high-level resistant mutants.

Buruli ulcer in Nigeria:results of a pilot case study in three rural districts

Background:Buruli ulcer(BU),also known as Mycobacterium ulcerans disease,is the third most common mycobacterial disease worldwide.Although BU disease has been diagnosed among Nigerians in neighbouring West African countries,data on the burden of the disease in Nigeria itself are scanty.This study aimed to assess the magnitude and epidemiology of BU in the South South region of Nigeria.Methods:We conducted a cross-sectional survey in the Ogoja territory(comprising 31 communities).We undertook sensitisation programmes centred on BU in 10 of the communities.Participants were asked to identify community members with long-standing ulcers,who were then invited for evaluation.We also contacted traditional healers to refer their clients who had non-healing ulcers.All suspected cases had a full clinical evaluation and laboratory testing.Confirmed cases were given treatment in a referral hospital in the territory.Results:We diagnosed 41 clinical BU cases;36(87.8%)of which were confirmed by quantitative polymerase chain reaction(qPCR).These 36 PCR-confirmed cases were diagnosed in a total population of 192,169 inhabitants.Therefore,the estimated crude prevalence of BU was 18.7 per 100,000 population,varying from 6.0 to 41.4 per 100,000 in the districts surveyed.The majority(66.7%)of the cases were females.About 92%of the BU lesions were located on the patients’extremities.No differences were observed between the sexes in terms of the location of the lesions.The age of the patients ranged from four to 60 years,with a median age of 17 years.All 35(100%)patients who consented to treatment completed chemotherapy as prescribed.Of the treated cases,29(82.9%)needed and received surgery.All cases healed,but 29(82.9%)had some limitations in movement.Healing with limitations in movement occurred in 18/19(94.7%)and 8/10(80.0%)of patients with lesions>15 cm(Category III)and 6–15 cm in diameter(Category II),respectively.The median duration of treatment was 130(87–164)days for children and 98(56–134)days for adults(p=0.15).Conclusions:In Nigeria,BU is endemic but its severity is underestimated—at least in the study setting.There is a need to identify and map BU endemic regions in Nigeria.A comprehensive BU control programme is also urgently needed.

溃疡分支杆菌引发Buruli溃疡的诊断与治疗(附6例报告并文献复习)(英文)

目的描述Buruli溃疡的病理、病原体的形态特征以及治疗特点,以提高对本病的认识。方法复习有关文献,根据临床和病理分析6例下肢及上肢慢性溃疡病人,按照WHO诊断标准作出临床诊断,并皆经病理和PCR检测证实。溃疡采用切除加植皮术治疗。结果5例单发溃疡中左下肢4例,右下肢1例。1例为多发溃疡,病变位于左右下肢及左食指。溃疡直径2.5-6.5cm,平均3.2cm。其特点是皮肤及皮下组织坏死,边缘呈潜行性,底部有黄色坏死物覆盖。溃疡周围皮肤水肿和色素沉着。显微镜下见到细胞外有散在或成团的抗酸杆菌和坏死脂肪细胞-“鬼影细胞”。抗结核药物和抗生素对本组Buruli溃疡无较,5例行手术切除溃疡加植皮术或清创术,除1例复发外,4例治疗效果良好。另1例行清创术换药后溃疡愈合。结论Buruli溃疡可以在我国的亚热带地区发生,因此当遇到久经不愈的慢性皮肤溃疡时,要考虑患有Buruli溃疡的可能性。外科手术仍然是目前治疗Buruli溃疡的主要方法。

分枝杆菌毒素——分枝杆菌内酯与布鲁里溃疡

溃疡分枝杆菌感染会导致慢性皮肤疾病布鲁里溃疡,引起组织坏死、细胞凋亡和免疫抑制等,感染前期患处会失去痛感从而往往使患者延迟其治疗。聚酮类分子分枝杆菌内酯是其细胞毒性的物质基础,也是分枝杆菌产生的主要毒素,对于免疫细胞和非免疫细胞都具有细胞毒性。本文综述了分枝杆菌内酯的结构、细胞毒性作用和分子靶点等,并提出了有待研究的问题以及研究意义。