Secondary Buruli Ulcer Skin Lesions Emerging Several Months after Completion of Chemotherapy: Paradoxical Reaction or Evidence for Immune Protection?

Abstract

BackgroundThe 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 FindingsWe 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/SignificanceOur 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.

Challenges Associated with Management of Buruli Ulcer/Human Immunodeficiency Virus Coinfection in a Treatment Center in Ghana: A Case Series Study

“…13,14 Laboratory and radiological investigations. Baseline complete blood count, liver function test, blood urea electrolytes and creatinine, erythrocyte sedimentation rate, fasting blood sugar and sickling test with/without Hb electrophoresis as indicated were done for all patients.…”

“…12 Some studies have reported paradoxical reactions in BU patients, which is defined as an increase in lesion size of 100% after initial improvement, and/or the appearance of a new lesion(s) following or during antimycobacterial treatment. 13,14 Currently, it is not clear whether immune reconstitution inflammatory syndrome (IRIS)-like mechanisms, secondary infections, 15 or other mechanisms are primarily responsible for impaired wound healing and deterioration of lesions during and after SR treatment in some of the BU patients. A retrospective study conducted in Cameroon revealed that human immunodeficiency virus (HIV) infection may affect the clinical presentation and severity of BU disease with a reported increased incidence of multiple, larger, and ulcerated BU lesions.…”

“…28,29 Despite this breakthrough 30 In the presence of a treated or ongoing opportunistic infection such as TB, such paradoxical IRIS could occur in which case it would be defined as 1) a new, worsening or recurrent sign or symptom consistent with an exaggerated or atypical inflammatory reaction to the previously diagnosed opportunistic infection, 2) the exclusion of medication toxicity or other disease processes as the cause of the abnormal event, and 3) a supportive evidence be it by some specialized imaging or histopathology. 31 The combined effect of the IRIS associated with HIV patients on ART 30 and the paradoxical reaction experienced in BU patients on antimicrobial treatment 13,14 could possibly pose a challenge to the management of BU/HIV coinfection.…”

Management of HIV Infected Patients with Active Buruli Ulcer in Tropical Regions in Africa, a New Therapeutic Challenge: A Review

“…These paradoxical reactions or inflammatory reconstitution immune syndrome (IRIS) usually, occurs 2 to 12 weeks after the initial antimicrobial treatment, although some may commence much later over 1 year after the end of treatment [12][13][14] . Clinically, lesions may seem to worsen after initial improvement, new lesions may appear, sometimes on a different part of the body, and non-ulcerative forms, such as nodules (or swelling), plaque and edema, may ulcerate.…”

“…In HIV/TB co-infection, the incidence of TB associated IRIS in increased in those start high active antiretroviral therapy (HAART) within 30 days of commencing TB treatment [4,12] . This could be extrapolated to Bu treatment in HIV-positive to explain the occurrence of IRIS in these patients.…”