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.

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.