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Spontaneous healing of Mycobacterium ulcerans disease in Australian patients

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      Abstract

      Background

      Mycobacterium ulcerans causes necrotising infections of skin and soft tissue mediated by the polyketide exotoxin mycolactone that causes cell apoptosis and immune suppression. It has been postulated that infection can be eradicated before the development of clinical lesions but spontaneous resolution of clinical lesions has been rarely described.

      Methodology/Principal findings

      We report a case series of five Australian patients who achieved healing of small M. ulcerans lesions without antibiotics or surgery. The median age of patients was 47 years (IQR 30–68 years) and all patients had small ulcerative lesions (median size 144mm 2, IQR 121-324mm 2). The median duration of symptoms prior to diagnosis was 90 days (IQR 90–100 days) and the median time to heal from diagnosis without treatment was 68 days (IQR 63–105 days). No patients recurred after a median follow-up of 16.6 months (IQR 16.6–17.9 months) from the development of symptoms and no patients suffered long-term disability from the disease.

      Conclusions

      We have shown that healing without specific treatment can occur for small ulcerated M. ulcerans lesions suggesting that in selected cases a robust immune response alone can cure lesions. Further research is required to determine what lesion and host factors are associated with spontaneous healing, and whether observation alone is an effective and safe form of management for selected small M. ulcerans lesions.

      Author summary

      Mycobacterium ulcerans causes a destructive infection of skin and soft tissue known as Buruli ulcer that when severe can lead to serious long-term deformity and disability. It is currently not well documented whether people with Mycobacterium ulcerans disease can cure themselves without treatment. In our study we describe five people with small ulcers who cured their disease without specific medical or surgical treatment. This suggests that a proportion of people can develop an immune response sufficient enough to eradicate the disease without the help of medical intervention. This is an important step, as recognition of this possibility provides important further insights into the human immune response against the disease. It also opens the possibility to further studies that may determine characteristics of the organism and hosts that favour spontaneous healing of lesions. This knowledge may in turn improve efforts to prevent and control the disease which are currently lacking.

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      Most cited references 25

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      Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial.

      Surgical debridement was the standard treatment for Mycobacterium ulcerans infection (Buruli ulcer disease) until WHO issued provisional guidelines in 2004 recommending treatment with antimicrobial drugs (streptomycin and rifampicin) in addition to surgery. These recommendations were based on observational studies and a small pilot study with microbiological endpoints. We investigated the efficacy of two regimens of antimicrobial treatment in early-stage M ulcerans infection. In this parallel, open-label, randomised trial undertaken in two sites in Ghana, patients were eligible for enrolment if they were aged 5 years or older and had early (duration <6 months), limited (cross-sectional diameter <10 cm), M ulcerans infection confirmed by dry-reagent-based PCR. Eligible patients were randomly assigned to receive intramuscular streptomycin (15 mg/kg once daily) and oral rifampicin (10 mg/kg once daily) for 8 weeks (8-week streptomycin group; n=76) or streptomycin and rifampicin for 4 weeks followed by rifampicin and clarithromycin (7.5 mg/kg once daily), both orally, for 4 weeks (4-week streptomycin plus 4-week clarithromycin group; n=75). Randomisation was done by computer-generated minimisation for study site and type of lesion (ulceration or no ulceration). The randomly assigned allocation was sent from a central site by cell-phone text message to the study coordinator. The primary endpoint was lesion healing at 1 year after the start of treatment without lesion recurrence or extensive surgical debridement. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00321178. Four patients were lost to follow-up (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, three). Since these four participants had healed lesions at their last assessment, they were included in the analysis for the primary endpoint. 73 (96%) participants in the 8-week streptomycin group and 68 (91%) in the 4-week streptomycin plus 4-week clarithromycin group had healed lesions at 1 year (odds ratio 2.49, 95% CI 0.66 to infinity; p=0.16, one-sided Fisher's exact test). No participants had lesion recurrence at 1 year. Three participants had vestibulotoxic events (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, two). One participant developed an injection abscess and two participants developed an abscess close to the initial lesion, which was incised and drained (all three participants were in the 4-week streptomycin plus 4-week clarithromycin group). Antimycobacterial treatment for M ulcerans infection is effective in early, limited disease. 4 weeks of streptomycin and rifampicin followed by 4 weeks of rifampicin and clarithromycin has similar efficacy to 8 weeks of streptomycin and rifampicin; however, the number of injections of streptomycin can be reduced by switching to oral clarithromycin after 4 weeks. European Union (EU FP6 2003-INCO-Dev2-015476) and Buruli Ulcer Groningen Foundation. Copyright 2010 Elsevier Ltd. All rights reserved.
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        Socioeconomic implications of Buruli ulcer in Ghana: a three-year review.

        This study examines some of the socioeconomic cost of treating 102 cases of Buruli ulcer between 1994 and 1996 at the St. Martin's Catholic Hospital in Agroyesum in the Amansie West district of the Ashanti region of Ghana. Seventy percent of the cases were children (up to 15 years of age). There was no sex difference in the distribution of cases. Hospitalization was prolonged (average = 186 days in 1994, 103 days in 1995, and 102 days in 1996) with no significant age and sex differences. There were 10 limb amputations, 12 patients were left with contracture deformities, one patient lost sight in one eye, and two died of sepsis and tetanus. The average total treatment cost per patient was $966.85 (62% indirect) in 1994, $706.08 (75% indirect) in 1995, and $658.74 (79% indirect) in 1996. With increasing number of cases, high treatment costs, and serious complications, urgent attention should be given to the disease in terms of control and research efforts aimed at early detection and treatment.
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          Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone

          Mycolactone is a polyketide toxin produced by Mycobacterium ulcerans (Mu), the causative agent of the skin disease Buruli ulcer (BU). Surprisingly, infected tissues lack inflammatory infiltrates. Structural similarities between mycolactone and immunosuppressive agents led us to investigate the immunomodulatory properties of mycolactone on dendritic cells (DCs), the key initiators and regulators of immune responses. At noncytotoxic concentrations, phenotypic and functional maturation of both mouse and human DCs was inhibited by mycolactone. Notably, mycolactone blocked the emigration of mouse-skin DCs to draining lymph nodes, as well as their maturation in vivo. In human peripheral blood–derived DCs, mycolactone inhibited the ability to activate allogeneic T cell priming and to produce inflammatory molecules. Interestingly, production of the cytokines interleukin (IL) 12, tumor necrosis factor α, and IL-6 was only marginally affected, whereas production of the chemokines macrophage inflammatory protein (MIP) 1α, MIP-1β, regulated on activation, normal T cell expressed and secreted, interferon γ–inducible protein 10, and monocyte chemoattractant protein 1 was abolished at nanomolar concentrations. Importantly, mycolactone endogenously expressed by Mu mediated similar inhibitory effects on β-chemokine production by DCs. In accordance with the histopathological features of BUs, our results suggest that bacterial production of mycolactone may limit both the initiation of primary immune responses and the recruitment of inflammatory cells to the infection site. Moreover, they highlight a potential interest in mycolactone as a novel immunosuppressive agent.
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            Author and article information

            Affiliations
            [1 ] Department of Infectious Diseases, Barwon Health, Geelong, Victoria, Australia
            [2 ] Department of Medicine and Infectious Diseases, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
            [3 ] Sorrento Medical Centre, Sorrento, Victoria, Australia
            [4 ] South Coast Medical, Blairgowrie, Victoria, Australia
            [5 ] Ocean Grove Medical Center, Ocean Grove, Victoria, Australia
            Swiss Tropical and Public Health Institute, SWITZERLAND
            Author notes

            The authors have declared that no competing interests exist.

            Contributors
            ORCID: http://orcid.org/0000-0001-5418-3330, Role: Conceptualization, Role: Data curation, Role: Formal analysis, Role: Investigation, Role: Methodology, Role: Writing – original draft, Role: Writing – review & editing
            Role: Writing – review & editing
            Role: Writing – review & editing
            ORCID: http://orcid.org/0000-0002-0029-4796, Role: Writing – review & editing
            Role: Writing – review & editing
            Role: Writing – review & editing
            Role: Editor
            Journal
            PLoS Negl Trop Dis
            PLoS Negl Trop Dis
            plos
            plosntds
            PLoS Neglected Tropical Diseases
            Public Library of Science (San Francisco, CA USA )
            1935-2727
            1935-2735
            19 February 2019
            February 2019
            : 13
            : 2
            30779807
            6396929
            10.1371/journal.pntd.0007178
            PNTD-D-18-01647
            (Editor)
            © 2019 O’Brien et al

            This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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            Figures: 2, Tables: 1, Pages: 8
            Product
            Funding
            The author(s) received no specific funding for this work.
            Categories
            Research Article
            Medicine and Health Sciences
            Diagnostic Medicine
            Signs and Symptoms
            Lesions
            Medicine and Health Sciences
            Pathology and Laboratory Medicine
            Signs and Symptoms
            Lesions
            Biology and Life Sciences
            Organisms
            Bacteria
            Actinobacteria
            Mycobacterium Ulcerans
            Biology and Life Sciences
            Physiology
            Physiological Processes
            Tissue Repair
            Medicine and Health Sciences
            Physiology
            Physiological Processes
            Tissue Repair
            Medicine and Health Sciences
            Pharmacology
            Drugs
            Antimicrobials
            Antibiotics
            Biology and Life Sciences
            Microbiology
            Microbial Control
            Antimicrobials
            Antibiotics
            Medicine and Health Sciences
            Surgical and Invasive Medical Procedures
            Biology and Life Sciences
            Immunology
            Immune Response
            Medicine and Health Sciences
            Immunology
            Immune Response
            Medicine and Health Sciences
            Diagnostic Medicine
            Medicine and Health Sciences
            Dermatology
            Skin Infections
            Medicine and Health Sciences
            Infectious Diseases
            Skin Infections
            Custom metadata
            vor-update-to-uncorrected-proof
            2019-03-01
            All relevant data are within the manuscript and its Supporting Information files.

            Infectious disease & Microbiology

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