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Background: We investigated the relationship between bacterial load in Buruli ulcer (BU) lesions and the development of paradoxical reaction following initiation of antibiotic treatment. Methods: This was a longitudinal study involving BU patients from June 2013 to June 2017. Fine needle aspirates (FNA) and swab samples were obtained to establish the diagnosis of BU by PCR. Additional samples were obtained at baseline, during and after treatment (if the lesion had not healed) for microscopy, culture and combined 16S rRNA reverse transcriptase/ IS2404 qPCR assay. Patients were followed up at regular intervals until complete healing. Results: Forty-seven of 354 patients (13%) with PCR confirmed BU had a PR, occurring between 2 and 42 (median 6) weeks after treatment initiation. The bacterial load, the proportion of patients with positive M. ulcerans culture (15/34 (44%) vs 29/119 (24%), p = 0.025) and the proportion with positive microscopy results (19/31 (61%) vs 28/90 (31%), p = 0.003) before initiation of treatment were significantly higher in the PR compared to the no PR group. Plaques (OR 5.12; 95% CI 2.26–11.61; p<0.001), oedematous (OR 4.23; 95% CI 1.43–12.5; p = 0.009) and category II lesions (OR 2.26; 95% CI 1.14–4.48; p = 0.02) were strongly associated with the occurrence of PR. The median time to complete healing (28 vs 13 weeks, p <0.001) was significantly longer in the PR group. Conclusions: Buruli ulcer patients who develop PR are characterized by high bacterial load in lesion samples taken at baseline and a higher rate of positive M. ulcerans culture. Occurrence of a PR was associated with delayed healing. Trial registration: ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

Background: Buruli Ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans. Former BU patients may experience participation restrictions due to physical limitations, stigmatization and other social factors. A scale that measures participation restrictions among children, who represent almost half of the affected population, has not been developed yet. Here, we present the development of a scale that measures participation restrictions in former BU paediatric patients, the psychometric properties of this scale and the scales’ results. Methods: Items were selected and a scale was developed based on interviews with health care workers and former BU patients in and around the BU treatment centre in Lalo, Benin. Construct validity was tested using six a priori formulated hypotheses. Former BU patients under 15 years of age who received treatment in one of the BU treatment centres in Ghana and Benin between 2007–2012 were interviewed. Results: A feasible 16-item scale that measures the concept of participation among children under 15 years of age was developed. In total, 109 (Ghana) and 90 (Benin) former BU patients were interviewed between 2012–2017. Five construct validity hypotheses were confirmed of which 2 hypotheses related to associations with existing questionnaires were statistically significant (p<0.05). In Ghana 77% of the former patients had a Paediatric Participation (PP) scale score of 0 compared to 22% in Benin. More severe lesions related to BU were seen in Benin. Most of the reported participation problems were related to sports, mainly in playing games with others, going to the playfield and doing sports at school. Conclusion: The preliminary results of the PP-scale validation are promising but further validation is needed. The developed PP-scale may be valid for use in patients with more severe BU lesions. This is the first research to confirm that former BU patients under 15-year face participation restrictions in important aspects of their lives. [ABSTRACT FROM AUTHOR]

Background: Buruli ulcer disease (BUD), caused by Mycobacterium (M.) ulcerans, is the third most common mycobacterial disease after tuberculosis and leprosy. BUD causes necrotic skin lesions and is a significant problem for health care in the affected countries. As for other mycobacterial infections, T cell mediated immune responses are important for protection and recovery during treatment, but detailed studies investigating these immune responses in BUD patients are scarce. In this study, we aimed to characterise M. ulcerans-specific CD4+ T cell responses in BUD patients and to analyse specific cytokine-producing T cells in the context of disease severity and progression. Methodology/Principal findings: For this case-control study, whole blood samples of BUD patients (N = 36, 1.5–17 years of age) and healthy contacts (N = 22, 3–15 years of age) were stimulated with antigen prepared from M. ulcerans and CD4+ T cells were analysed for the expression of TNFα, IFNγ and CD40L by flow cytometry. The proportions and profile of cytokine producing CD4+ T cells was compared between the two study groups and correlated with disease progression and severity. Proportions of cytokine double-positive IFNγ+TNFα+, TNFα+CD40L+, IFNγ+CD40L+ (p = 0.014, p = 0.010, p = 0.002, respectively) and triple positive IFNγ+TNFα+CD40L+ (p = 0.010) producing CD4+ T cell subsets were increased in BUD patients. In addition, TNFα+CD40L-IFNγ- CD4+ T cells differed between patients and controls (p = 0.034). TNFα+CD40L-IFNγ- CD4+ T cells were correlated with lesion size (p = 0.010) and proportion were higher in ‘slow’ healers compared to ‘fast healers’ (p = 0.030). Conclusions: We were able to identify M. ulcerans-specific CD4+ T cell subsets with specific cytokine profiles. In particular a CD4+ T cell subset, producing TNFα but not IFNγ and CD40L, showed association with lesion size and healing progress. Further studies are required to investigate, if the identified CD4+ T cell subset has the potential to be used as biomarker for diagnosis, severity and/or progression of disease. [ABSTRACT FROM AUTHOR]

Background: Buruli ulcer (BU), caused by Mycobacterium ulcerans, is a neglected tropical disease frequently leading to permanent disabilities. The ulcers are treated with rifampicin and streptomycin, wound care and, if necessary surgical intervention. Professionals have exclusively shaped the research agenda concerning management and control, while patients’ perspective on priorities and preferences have not explicitly been explored or addressed. Methodology/Principal findings: To get insight into patient perception of the management and control of Buruli ulcer a mixed methods research design was applied with a questionnaire and focus group discussions among former BU patients. Data collection was obtained in collaboration with a local team of native speakers in Ghana. A questionnaire was completed by 60 former patients and four focus group discussions were conducted with eight participants per group. Former patients positively evaluated both the effectiveness of the treatment and the financial contribution received for the travel costs to the hospitals. Pain experienced during treatment procedures, in particular wound care and the streptomycin injections, and the side-effects of the treatment were negatively evaluated. Former patients considered the development of preventive measures and knowledge on the transmission as priorities. Additionally, former patients asked for improved accessibility of health services, counselling and economic support. Conclusions: These findings can be used to improve clinical management and to guide the international research agenda. [ABSTRACT FROM AUTHOR]

Introduction: Buruli ulcer (BU) is the third most frequent mycobacterial disease in immunocompetent persons after tuberculosis and leprosy. During the last decade, eight weeks of antimicrobial treatment has become the standard of care. This treatment may be accompanied by transient clinical deterioration, known as paradoxical reaction. We investigate the incidence and the risks factors associated with paradoxical reaction in BU. Methods: The lesion size of participants was assessed by careful palpation and recorded by serial acetate sheet tracings. For every time point, surface area was compared with the previous assessment. All patients received antimicrobial treatment for 8 weeks. Serum concentration of 25-hydroxyvitamin D, the primary indicator of vitamin D status, was determined in duplex for blood samples at baseline by a radioimmunoassay. We genotyped four polymorphisms in the SLC11A1 gene, previously associated with susceptibility to BU. For testing the association of genetic variants with paradoxical responses, we used a binary logistic regression analysis with the occurrence of a paradoxical response as the dependent variable. Results: Paradoxical reaction occurred in 22% of the patients; the reaction was significantly associated with trunk localization (p = .039 by Χ2), larger lesions (p = .021 by Χ2) and genetic factors. The polymorphisms 3’UTR TGTG ins/ins (OR 7.19, p < .001) had a higher risk for developing paradoxical reaction compared to ins/del or del/del polymorphisms. Conclusions: Paradoxical reactions are common in BU. They are associated with trunk localization, larger lesions and polymorphisms in the SLC11A1 gene. [ABSTRACT FROM AUTHOR]

Background: Buruli Ulcer is a tropical skin disease caused by Mycobacterium ulcerans, which, due to scarring and contractures can lead to stigma and functional limitations. However, recent advances in treatment, combined with increased public health efforts have the potential to significantly improve disease outcome. Objectives: To study the Quality of Life (QoL) of former Buruli Ulcer patients who, in the context of a randomized controlled trial, reported early with small lesions (cross-sectional diameter <10 cm), and received a full course of antibiotic treatment. Methods: 127 Participants of the BURULICO drug trial in Ghana were revisited. All former patients aged 16 or older completed the Dermatology Life Quality Index (DLQI) and the abbreviated World Health Organization Quality of Life scale (WHOQOL-BREF). The WHOQOL-BREF was also administered to 82 matched healthy controls. Those younger than 16 completed the Childrens' Dermatology Life Quality Index (CDLQI) only. Results: The median (Inter Quartile Range) score on the DLQI was 0 (0–4), indicating good QoL. 85% of former patients indicated no effect, or only a small effect of the disease on their current life. Former patients also indicated good QoL on the physical and psychological domains of the WHOQOL-BREF, and scored significantly higher than healthy controls on these domains. There was a weak correlation between the DLQI and scar size (ρ = 0.32; p<0.001). Conclusions: BU patients who report early with small lesions and receive 8 weeks of antimicrobial therapy have a good QoL at long-term follow-up. These findings contrast with the debilitating sequelae often reported in BU, and highlight the importance of early case detection. [ABSTRACT FROM AUTHOR]

Buruli ulcer is a skin disease caused by Mycobacterium ulcerans that is spreading in tropical countries, with major public health and economic implications in West Africa. Multi-analyte profiling of serum proteins in patients and endemic controls revealed that Buruli ulcer disease down-regulates the circulating levels of a large array of inflammatory mediators, without impacting on the leukocyte composition of peripheral blood. Notably, several proteins contributing to acute phase reaction, lipid metabolism, coagulation and tissue remodelling were also impacted. Their down-regulation was selective and persisted after the elimination of bacteria with antibiotic therapy. It involved proteins with various functions and origins, suggesting that M. ulcerans infection causes global and chronic defects in the host's protein metabolism. Accordingly, patients had reduced levels of total serum proteins and blood urea, in the absence of signs of malnutrition, or functional failure of liver or kidney. Interestingly, slow healers had deeper metabolic and coagulation defects at the start of antibiotic therapy. In addition to providing novel insight into Buruli ulcer pathogenesis, our study therefore identifies a unique proteomic signature for this disease. [ABSTRACT FROM AUTHOR]