title: Secondary Buruli ulcer skin lesions emerging several months after completion of chemotherapy: paradoxical reaction or evidence for immune protection?
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Ruf
authors.forename: Annick
authors.initials: A
authors.lastname: Chauty
authors.forename: Ambroise
authors.initials: A
authors.lastname: Adeye
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Ardant
authors.forename: Hugues
authors.initials: H
authors.lastname: Koussemou
authors.forename: Roch Christian
authors.initials: RC
authors.lastname: Johnson
authors.forename: Gerd
authors.initials: G
authors.lastname: Pluschke
mesh_terms: D000904:Antibiotics, Antitubercular / Q000008:administration & dosage; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D054312:Buruli Ulcer / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002648:Child; D006801:Humans; D007150:Immunohistochemistry; D007962:Leukocytes / Q000276:immunology; D008297:Male; D019911:Mycobacterium ulcerans / Q000302:isolation & purification*; D009336:Necrosis / Q000473:pathology; D058069:Neglected Diseases; D012293:Rifampin / Q000008:administration & dosage*; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013307:Streptomycin / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000904:Antibiotics, Antitubercular; D015703:Antigens, CD; D012293:Rifampin; D013307:Streptomycin