Date Published: September 10, 2015
Publisher: Public Library of Science
Author(s): Carlos Capela, Ghislain E. Sopoh, Jean G. Houezo, René Fiodessihoué, Ange D. Dossou, Patrício Costa, Alexandra G. Fraga, João F. Menino, Rita Silva-Gomes, Edgard M. Ouendo, Fernando Rodrigues, Jorge Pedrosa, Christian Johnson. http://doi.org/10.1371/journal.pntd.0004005
Abstract: Buruli Ulcer (BU) is a neglected infectious disease caused by Mycobacterium ulcerans that is responsible for severe necrotizing cutaneous lesions that may be associated with bone involvement. Clinical presentations of BU lesions are classically classified as papules, nodules, plaques and edematous infiltration, ulcer or osteomyelitis. Within these different clinical forms, lesions can be further classified as severe forms based on focality (multiple lesions), lesions’ size (>15cm diameter) or WHO Category (WHO Category 3 lesions). There are studies reporting an association between delay in seeking medical care and the development of ulcerative forms of BU or osteomyelitis, but the effect of time-delay on the emergence of lesions classified as severe has not been addressed. To address both issues, and in a cohort of laboratory-confirmed BU cases, 476 patients from a medical center in Allada, Benin, were studied. In this laboratory-confirmed cohort, we validated previous observations, demonstrating that time-delay is statistically related to the clinical form of BU. Indeed, for non-ulcerated forms (nodule, edema, and plaque) the median time-delay was 32.5 days (IQR 30.0–67.5), while for ulcerated forms it was 60 days (IQR 20.0–120.0) (p = 0.009), and for bone lesions, 365 days (IQR 228.0–548.0). On the other hand, we show here that time-delay is not associated with the more severe phenotypes of BU, such as multi-focal lesions (median 90 days; IQR 56–217.5; p = 0.09), larger lesions (diameter >15cm) (median 60 days; IQR 30–120; p = 0.92) or category 3 WHO classification (median 60 days; IQR 30–150; p = 0.20), when compared with unifocal (median 60 days; IQR 30–90), small lesions (diameter ≤15cm) (median 60 days; IQR 30–90), or WHO category 1+2 lesions (median 60 days; IQR 30–90), respectively. Our results demonstrate that after an initial period of progression towards ulceration or bone involvement, BU lesions become stable regarding size and focal/multi-focal progression. Therefore, in future studies on BU epidemiology, severe clinical forms should be systematically considered as distinct phenotypes of the same disease and thus subjected to specific risk factor investigation.
Partial Text: Buruli ulcer (BU), caused by Mycobacterium ulcerans, is the third most common mycobacteriosis worldwide, after tuberculosis and leprosy . BU pathogenesis is mediated by mycolactone, a potent polyketide-derived macrolide that triggers apoptotic cell death  and is associated with the necrotic nature of the disease . BU mostly affects people in tropical countries in Africa , America , Asia  and Australia . Although no official estimate of global incidence is available at present, West Africa is the main endemic area, with 1967 new cases reported by Côte d’Ivoire, Ghana, and Benin in 2013. BU is a devastating necrotising skin infection characterised by pre-ulcerative lesions (papules, nodules, plaques and edematous infiltration), which commonly develop into ulcers with undermined edges and can spread to an entire limb  and can also affect the bone (osteomyelitis) . Moreover, within these clinical presentations, more aggressive severe forms of BU, such as multiple lesions, larger lesions or higher World Health Organization (WHO) categories have been described , although underreported and less understood. Epidemiological studies on M. ulcerans transmission, on BU risk factors and on the host immune status, suggest that the variable frequency of BU and its distinct clinical forms are related to: i) age; ii) gender; iii) preferential anatomical site; iv) water contact; and v) regional occurrences [12,13,14,15,16].
BU pathogenesis is related with necrosis of the subcutaneous tissue associated with mycolactone, the potent cytotoxic/immunosuppressive toxin produced by M. ulcerans . Initial pre-ulcerative lesions (papules, nodules, plaques and edematous infiltration) can evolve into ulcers and progressively spread over significant extensions of the body  or even affect the bone . Large national studies in West African countries, namely Ghana , Benin [28,29,32] and Côte D`Ivoire , included the largest BU cohorts studied thus far and provided information about the age and gender of patients, site of lesions and the major clinical forms—providing further clues on the evolution of BU pathology. The majority of these studies used distinct methodologies (retrospective and/or prospective cohorts; cross-sectional) and a descriptive approach, with a large proportion of diagnoses being retrospective and scar-based. Here, we strictly consider laboratory-confirmed BU patients.