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Mycobacterium ulcerans causes Buruli ulcer, the third most frequent mycobacterial disease after tuberculosis and leprosy. Transient clinical deteriorations, known as paradoxical reactions, occur in some patients during or after antibiotic treatment. We investigated the clinical and biological features of PRs in a prospective cohort of BU patients from Benin including forty-one patients. Neutrophil counts decreased from baseline to day 90 and IL-6, G-CSF and VEGF were the cytokines displaying a significant monthly decrease relative to baseline. Paradoxical reactions occurred in 10 (24%) patients. The baseline biological and clinical characteristics of the patients presenting PRs did not differ significantly from those of the other patients. However, the patients with PRs had significantly higher IL-6 and TNF-α concentrations on days 30, 60 and 90 after the start of antibiotic treatment. The absence of a decrease in IL-6 and TNF-α levels during treatment should alert clinicians to the possibility of PR onset.

Here, we describe the first 10 years of activity at a field laboratory established at the Buruli ulcer treatment center (CDTLUB) in Pobè, Benin, a country in which Mycobacterium ulcerans is endemic. Between 2012 and 2022, the laboratory analyzed 3,018 samples from patients consulting the CDTLUB of Pobè with a suspected clinical BU.

BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions.METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437.FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts.INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer.FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.

According to recommendations of the 6th WHO Advisory Committee on Buruli ulcer, directly observed treatment with the combination of rifampin and streptomycin, administered daily for 8 weeks, was recommended to 310 patients diagnosed with Buruli ulcer in Pobè, Bénin. Among the 224 (72%) eligible patients for whom treatment was initiated, 215 (96%) were categorized as treatment successes, and 9, including 1 death and 8 losses to follow-up, were treatment failures. Of the 215 successfully treated patients, 102 (47%) were treated exclusively with antibiotics and 113 (53%) were treated with antibiotics plus surgical excision and skin grafting. The size of lesions at treatment initiation was the major factor associated with surgical intervention: 73% of patients with lesions of >15 cm in diameter underwent surgery, whereas only 17% of patients with lesions of Mycobacterium ulcerans disease, 2 among the 107 patients treated only with antibiotics and 1 among the 108 patients treated with antibiotics plus surgery. We conclude that the WHO-recommended streptomycin-rifampin combination is highly efficacious for treating M. ulcerans disease. Chemotherapy alone was successful in achieving cure in 47% of cases and was particularly effective against ulcers of less than 5 cm in diameter.

Mycobacterium ulcerans infection is responsible for severe skin lesions in sub-Saharan Africa. We enrolled 30 Beninese patients with Buruli ulcers in a pilot study to evaluate efficacy of an oral chemotherapy using rifampicin plus clarithromycin during an 8-week period. The treatment was well tolerated, and all patients were healed by 12 months after initiation of therapy without relapse.

No simple diagnostic tool is available to confirm Mycobacterium ulcerans infection, which is an emerging disease reported in many rural areas of Africa. Here, we report the 1-year results of a hospital laboratory that was created in an area of endemicity of Benin to facilitate the diagnosis of M. ulcerans infection.

International audience; Background. Mycobacterium ulcerans is known to cause Buruli ulcer (BU), a necrotizing skin disease leading to extensive cutaneous and subcutaneous destruction and functional limitations. However, M. ulcerans infections are not limited to skin, and osteomyelitis, still poorly described in the literature, occurs in numerous young patients in Africa.Methods. In a retrospective matched case-control study conducted in a highly endemic area in Benin, we analyzed demographic, clinical, biological, and radiological features in all patients with M. ulcerans infections with bone involvement, identified from a cohort of 1257 patients with polymerase chain reaction–proved M. ulcerans infections. Results. The 81 patients studied had a median age of 11 years (interquartile range, 7–16 years) and were predominantly male (male–female ratio, 2:1). Osteomyelitis was observed beneath active BU lesions (60.5%) or at a distance from active or apparently healed BU lesions (14.8%) but also in patients without a history of BU skin lesions (24.7%). These lesions had an insidious course, with nonspecific clinical findings leading to delayed diagnosis. A comparison with findings in 243 age- and sex-matched patients with BU without osteomyelitis showed that case patients were less likely to have received BCG immunization than controls (33.3% vs 52.7%; P = .01). They were also at higher risk of longer hospital stay (118 vs 69 days; P = .001), surgery (92.6% vs 63.0%; P = .001), and long-term crippling sequelae (55.6% vs 15.2%; P < .001). Conclusions. This study highlighted the difficulties associated with diagnosis of M. ulcerans osteomyelitis, with one-fourth of patients having no apparent history of BU skin lesions, including during the current course of illness. Delays in treatment contributed to the high proportion (55.6%) of patients with crippling sequelae.

International audience; We report here the clinical case of a Nigerian adult patient who received medical care during October 2010, at the Center for Diagnosis and Treatment of Buruli ulcer in Pobè (Benin). He presented a massive facial tumor associated with several subcutaneous (cervical, thoracic and upper limbs) nodules, evolving since several years. Tissue samples collected at Pobè medical center were addressed to the mycology and histology laboratories of Angers University Hospital (France), according to the medical exchange agreement between the two institutions about the diagnosis and treatment of Buruli ulcer disease. Histological examination showed a Splendore-Hoeppli phenomenon, consisting of a granulomatous reaction made of eosinophilic polynuclear cells surrounding rare, large and irregular, non-septate hyphae. A filamentous fungus was isolated by cultivation of the clinical samples, which was identified as Conidiobolus coronatus. The patient was treated orally with daily doses of ketoconazole (400mg per day). After 4months of treatment, a marked regression of the facial lesion was obtained. A first constructive facial surgery was achieved, but the patient did not attend the second step. This case report allows us to remind the mycological diagnosis of this exotic mycosis, but also to emphasize the main difficulties encountered in medical management in the developing countries.; Nous présentons ici l’observation d’un patient adulte originaire du Nigeria, qui a consulté en octobre 2010le Centre de diagnostic et de traitement de l’ulcère de Buruli de Pobè au Bénin, pour une tuméfaction importante du visage associée à des lésions nodulaires sous-cutanées localisées au cou, au thorax et aux membres supérieurs, évoluant depuis plusieurs années. Les prélèvements réalisés sur place ont été adressés aux laboratoires de parasitologie-mycologie et au département de pathologie cellulaire et tissulaire du CHU d’Angers, dans le cadre d’un contrat de collaboration sur le diagnostic de l’ulcère de Buruli. L’examen histologique des biopsies pratiquées sur les lésions d’un avant-bras a permis de mettre en évidence une réaction granulomateuse giganto-cellulaire à prédominance de polynucléaires éosinophiles, associée à la présence de rares éléments mycéliens larges et non septés, soulignés par un important phénomène de Splendore-Hoeppli. Un champignon filamenteux a été isolé à partir des milieux de culture ensemencés avec les fragments biopsiques cutanés, qui a ensuite été identifié comme étant un Conidiobolus coronatus. Le patient a été traité par du kétoconazole à raison de 400mg par jour. Après 4mois de traitement, une régression nette des lésions a été constatée. Une chirurgie réparatrice du visage n’a été réalisée que partiellement, le patient ayant refusé une deuxième intervention. Cette observation souligne les difficultés de diagnostic et de prise en charge des mycoses tropicales dans les pays en développement.

Background The neglected tropical disease Buruli ulcer (BU) caused by Mycobacterium ulcerans is an infection of the subcutaneous tissue leading to chronic ulcerative skin lesions. Histopathological features are progressive tissue necrosis, extracellular clusters of acid fast bacilli (AFB) and poor inflammatory responses at the site of infection. After the recommended eight weeks standard treatment with rifampicin and streptomycin, a reversal of the local immunosuppression caused by the macrolide toxin mycolactone of M. ulcerans is observed. Methodology/Principal Findings We have conducted a detailed histopathological and immunohistochemical analysis of tissue specimens from two patients developing multiple new skin lesions 12 to 409 days after completion of antibiotic treatment. Lesions exhibited characteristic histopathological hallmarks of Buruli ulcer and AFB with degenerated appearance were found in several of them. However, other than in active disease, lesions contained massive leukocyte infiltrates including large B-cell clusters, as typically found in cured lesions. Conclusion/Significance Our histopathological findings demonstrate that the skin lesions emerging several months after completion of antibiotic treatment were associated with M. ulcerans infection. During antibiotic therapy of Buruli ulcer development of new skin lesions may be caused by immune response-mediated paradoxical reactions. These seem to be triggered by mycobacterial antigens and immunostimulators released from clinically unrecognized bacterial foci. However, in particular the lesions that appeared more than one year after completion of antibiotic treatment may have been associated with new infection foci resolved by immune responses primed by the successful treatment of the initial lesion., Author Summary Buruli ulcer (BU) is a chronic necrotizing skin disease presenting with extensive tissue destruction and local immunosuppression. Standard treatment recommended by the WHO includes 8 weeks of rifampicin/streptomycin and, if necessary, wound debridement and skin grafting. In some patients satellite lesions develop close to the primary lesion or occasionally also at distant sites during effective antibiotic treatment of the primary lesion. We performed a detailed analysis of tissue specimens from lesions that emerged in two BU patients from Benin 12 to 409 days after completion of chemotherapy. Histopathology revealed features of tissue destruction typically seen in BU and degenerated acid-fast bacilli. In addition, lesions contained organized immune infiltrates typically found in successfully treated BU lesions. Secondary lesions emerging many months after completion of chemotherapy may have been caused by immune response-mediated paradoxical reactions. However, the late onset may also indicate that they were associated with new infection foci spontaneously resolved by adaptive immune responses primed by antibiotic treatment of the primary lesions.