30
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Spontaneous healing of Mycobacterium ulcerans disease in Australian patients

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references25

          • Record: found
          • Abstract: found
          • Article: not found

          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.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            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.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Sec61 blockade by mycolactone inhibits antigen cross-presentation independently of endosome-to-cytosol export.

              Although antigen cross-presentation in dendritic cells (DCs) is critical to the initiation of most cytotoxic immune responses, the intracellular mechanisms and traffic pathways involved are still unclear. One of the most critical steps in this process, the export of internalized antigen to the cytosol, has been suggested to be mediated by Sec61. Sec61 is the channel that translocates signal peptide-bearing nascent polypeptides into the endoplasmic reticulum (ER), and it was also proposed to mediate protein retrotranslocation during ER-associated degradation (a process called ERAD). Here, we used a newly identified Sec61 blocker, mycolactone, to analyze Sec61's contribution to antigen cross-presentation, ERAD, and transport of internalized antigens into the cytosol. As shown previously in other cell types, mycolactone prevented protein import into the ER of DCs. Mycolactone-mediated Sec61 blockade also potently suppressed both antigen cross-presentation and direct presentation of synthetic peptides to CD8+ T cells. In contrast, it did not affect protein export from the ER lumen or from endosomes into the cytosol, suggesting that the inhibition of cross-presentation was not related to either of these trafficking pathways. Proteomic profiling of mycolactone-exposed DCs showed that expression of mediators of antigen presentation, including MHC class I and β2 microglobulin, were highly susceptible to mycolactone treatment, indicating that Sec61 blockade affects antigen cross-presentation indirectly. Together, our data suggest that the defective translocation and subsequent degradation of Sec61 substrates is the cause of altered antigen cross-presentation in Sec61-blocked DCs.
                Bookmark

                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Writing – review & editing
                Role: Writing – review & editing
                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
                : e0007178
                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.

                Author information
                http://orcid.org/0000-0001-5418-3330
                http://orcid.org/0000-0002-0029-4796
                Article
                PNTD-D-18-01647
                10.1371/journal.pntd.0007178
                6396929
                30779807
                ed3ec95d-7bfa-4735-bbf2-649bb3dba8e1
                © 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.

                History
                : 28 October 2018
                : 22 January 2019
                Page count
                Figures: 2, Tables: 1, Pages: 8
                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
                Infectious disease & Microbiology

                Comments

                Comment on this article