ABSTRACT
BACKGROUND: Buruli ulcer (BU) is a necrotizing skin disease most prevalent among West African children. The causative organism, Mycobacterium ulcerans, is sensitive to temperatures above 37°C. We investigated the safety and efficacy of a local heat application device based on phase change material. METHODS: In a phase II open label single center noncomparative clinical trial (ISRCTN 72102977) under GCP standards in Cameroon, laboratory confirmed BU patients received up to 8 weeks of heat treatment. We assessed efficacy based on the endpoints 'absence of clinical BU specific features' or 'wound closure' within 6 months ("primary cure"), and 'absence of clinical recurrence within 24 month' ("definite cure"). RESULTS: Of 53 patients 51 (96%) had ulcerative disease. 62% were classified as World Health Organization category II, 19% each as category I and III. The average lesion size was 45 cm(2). Within 6 months after completion of heat treatment 92.4% (49 of 53, 95% confidence interval [CI], 81.8% to 98.0%) achieved cure of their primary lesion. At 24 months follow-up 83.7% (41 of 49, 95% CI, 70.3% to 92.7%) of patients with primary cure remained free of recurrence. Heat treatment was well tolerated; adverse effects were occasional mild local skin reactions. CONCLUSIONS: Local thermotherapy is a highly effective, simple, cheap and safe treatment for M. ulcerans disease. It has in particular potential as home-based remedy for BU suspicious lesions at community level where laboratory confirmation is not available. CLINICAL TRIALS REGISTRATION: ISRCT 72102977.
Subject(s)
Buruli Ulcer/therapy , Hyperthermia, Induced/methods , Cameroon , Child , Female , Hot Temperature , Humans , Hyperthermia, Induced/adverse effects , Male , Treatment OutcomeABSTRACT
BACKGROUND: Current laboratory diagnosis of Buruli ulcer (BU) is based on microscopic detection of acid fast bacilli, quantitative real-time PCR (qPCR), histopathology or cultivation. Insertion sequence (IS) 2404 qPCR, the most sensitive method, is usually only available at reference laboratories. The only currently available point-of-care test, microscopic detection of acid fast bacilli (AFB), has limited sensitivity and specificity. METHODOLOGY/ PRINCIPAL FINDINGS: Here we analyzed AFB positive tissue samples (n = 83) for the presence, distribution and amount of AFB. AFB were nearly exclusively present in the subcutis with large extracellular clusters being most frequently (67%) found in plaque lesions. In ulcerative lesions small clusters and dispersed AFB were more common. Beside this, 151 swab samples from 37 BU patients were analyzed by IS2404 qPCR and ZN staining in parallel. The amount of M. ulcerans DNA in extracts from swabs correlated well with the probability of finding AFB in direct smear microscopy, with 56.1% of the samples being positive in both methods and 43.9% being positive only in qPCR. By analyzing three swabs per patient instead of one, the probability to have at least one positive swab increased from 80.2% to 97.1% for qPCR and from 45% to 66.1% for AFB smear examination. CONCLUSION / SIGNIFICANCE: Our data show that M. ulcerans bacteria are primarily located in the subcutis of BU lesions, making the retrieval of the deep subcutis mandatory for examination of tissue samples for AFB. When laboratory diagnosis is based on the recommended less invasive collection of swab samples, analysis of three swabs from different areas of ulcerative lesions instead of one increases the sensitivity of both qPCR and of smear microscopy substantially.