title: Clinical epidemiology of laboratory-confirmed Buruli ulcer in Benin: a cohort study.
abstract: BACKGROUND
  Buruli ulcer, caused by Mycobacterium ulcerans, was identified as a neglected emerging infectious disease by WHO in 1998. Although Buruli ulcer is the third most common mycobacterial disease worldwide, understanding of the disease is incomplete. We analysed a large cohort of laboratory-confirmed cases of Buruli ulcer from Pobè, Benin, to provide a comprehensive description of the clinical presentation of the disease, its variation with age and sex, and its effect on the occurrence of permanent functional sequelae.
  
  
  METHODS
  Between Jan 1, 2005, and Dec 31, 2011, we prospectively collected clinical and laboratory data from all patients with Buruli ulcer diagnosed at the Centre de Dépistage et de Traitement de l'Ulcère de Buruli in Pobè, Benin. We followed up patients to assess the frequency of permanent functional sequelae. All analyses were done on cases that were laboratory confirmed.
  
  
  RESULTS
  1227 cases of laboratory-confirmed Buruli ulcer were included in the analysis. Typically, patients with Buruli ulcer were children (median age at diagnosis 12 years) presenting with a unique (1172 [96%]) large (≥15 cm, 444 [36%]) ulcerative (805 [66%]) lesion of the lower limb (733 [60%]). Atypical clinical presentation of Buruli ulcer included Buruli ulcer osteomyelitis with no identifiable present or past Buruli ulcer skin lesions, which was recorded in at least 14 patients. The sex ratio of Buruli ulcer widely varied with age, with male patients accounting for 57% (n=427) of patients aged 15 years and younger, but only 33% (n=158) of those older than 15 years (odds ratio [OR] 2·59, 95% CI 2·04-3·30). Clinical presentation of Buruli ulcer was significantly dependent on age and sex. 54 (9%) male patients had Buruli ulcer osteomyelitis, whereas only 28 (4%) of female patients did (OR 2·21, 95% CI 1·39-3·59). 1 year after treatment, 229 (22% of 1043 with follow-up information) patients presented with permanent functional sequelae. Presentation with oedema, osteomyelitis, or large (≥15 cm in diameter), or multifocal lesions was significantly associated with occurrence of permanent functional sequelae (OR 7·64, 95% CI 5·29-11·31) and operationally defines severe Buruli ulcer.
  
  
  CONCLUSIONS
  Our findings have important clinical implications for daily practice, including enhanced surveillance for early detection of osteomyelitis in boys; systematic search for M ulcerans in osteomyelitis cases of non-specific aspect in areas endemic for Buruli ulcer; and specific disability prevention for patients presenting with osteomyelitis, oedema, or multifocal or large lesions. Our findings also suggest a crucial underestimation of the burden of Buruli ulcer in Africa and raise key questions about the contribution of environmental and physiopathological factors to the recorded heterogeneity of the clinical presentation of Buruli ulcer.
  
  
  BACKGROUND
  Agence Nationale de la Recherche (ANR), Fondation Raoul Follereau, Fondation pour la Recherche Médicale (FRM), and Institut des Maladies Génétiques (IMAGINE).
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Recherche Médicale U1163 (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Quentin B
authors.initials: QB
authors.lastname: Vincent
authors.affiliation: Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB), Pobè, Benin; Fondation Raoul Follereau, Paris, France.
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Ardant
authors.affiliation: Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB), Pobè, Benin; Fondation Raoul Follereau, Paris, France.
authors.forename: Ambroise
authors.initials: A
authors.lastname: Adeye
authors.affiliation: Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB), Pobè, Benin; Fondation Raoul Follereau, Paris, France.
authors.forename: Aimé
authors.initials: A
authors.lastname: Goundote
authors.affiliation: Laboratoire d'Anatomie Pathologique, CHU d'Angers, Angers, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Saint-André
authors.affiliation: Laboratoire de Bactériologie, CHU d'Angers, Angers, France.
authors.forename: Jane
authors.initials: J
authors.lastname: Cottin
authors.affiliation: Laboratoire de Bactériologie, CHU d'Angers, Angers, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Kempf
authors.affiliation: Programme de Lutte Contre la Lèpre et l'Ulcère de Buruli, Ministère de la Santé, Cotonou, Bénin.
authors.forename: Didier
authors.initials: D
authors.lastname: Agossadou
authors.affiliation: Fondation Raoul Follereau, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Recherche Médicale U1163 (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Institut National de la Recherche Médicale U892 (INSERM) et CNRS U6299, Université et CHU d'Angers, Angers, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Marsollier
authors.affiliation: Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB), Pobè, Benin; Fondation Raoul Follereau, Paris, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Chauty
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Recherche Médicale U1163 (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA; Unité de Recherche Clinique, Paris Centre Descartes Necker Cochin, Assistance Publique- Hôpitaux de Paris, Paris, France. Electronic address: alexandre.alcais@inserm.fr.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
mesh_terms: D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D001541:Benin / Q000453:epidemiology; D054312:Buruli Ulcer / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology*; D015984:Causality; D002648:Child; D015331:Cohort Studies; D015897:Comorbidity; D004487:Edema / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D010019:Osteomyelitis / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D011446:Prospective Studies; D017678:Sex Distribution; D055815:Young Adult