Abass, MK

Abotsi, J

Asiedu, K

Frimpong, M

Paintsil, A

Phillips, RO

Sarfo, FS

Thompson, W

Wansbrough-Jones, MH

PLoS Neglected Tropical Diseases

English

PubMed

Fred S. Sarfo

William Thompson

Richard O. Phillips

Albert Paintsil

Mohammed K. Abass

Michael Frimpong

Justice Abotsi

Kingsley Asiedu

Mark H. Wansbrough-Jones

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A Severe Case of Buruli Ulcer Disease with Pleural Effusions

Fred S Sarfo

Richard O Phillips

Mohammed K Abass

Mark H Wansbrough-Jones

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A severe case of Buruli ulcer disease with pleural effusions.

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SymposiumA Severe Case of Buruli Ulcer Disease with PleuralEffusionsFred S. Sarfo1,2*, William Thompson3, Richard O. Phillips1,2, Albert Paintsil4, Mohammed K. Abass3,Michael Frimpong5, Justice Abotsi3, Kingsley Asiedu6, Mark H. Wansbrough-Jones71 Komfo Anokye Teaching Hospital, Kumasi, Ghana, 2 School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana, 3AgogoPresbyterian Hospital, Ministry of Health, Agogo, Ghana, 4 Korle-Bu Teaching Hospital, Accra, Ghana, 5 Kumasi Center for Collaborative Research, Kumasi, Ghana, 6WorldHealth Organisation, Geneva, Switzerland, 7 St. George’s University of London, London, United KingdomPresentation of CasePatient GO is an 8-year-old studentfrom Drobonso, a Buruli ulcer–endemiccommunity in the Sekyere Afram Plainsof the Ashanti region of Ghana. Shepresented with a month’s history of apainless nodule on the anterior chestwhich started increasing in size rapidlyover the course of two weeks. Afterapplying herbal preparations on the lesionand observing no improvement in symp-toms, she sought medical attentionthrough which a course of oral amoxycil-lin was prescribed for a week. However,her lesion continued to enlarge withinvolvement of her anterior and posteriorchest walls and ulcerations over the leftanterior cervical triangle and midsternalregion. Upon the recommendation of aformer patient from the same endemicregion, she came to the Buruli ulcer clinicat the Agogo Presbyterian Hospital on the24th of February 2011. On examination,the patient looked fairly stable and wasafebrile (36.9uC), not pale, and anictericwith no regional lymphadenopathy. Herchest was clinically clear with a respira-tory rate of 14 cycles/min. The mostsignificant finding was an extensive oe-dematous lesion involving the chest andneck regions with two deep ulcerations(Figure 1). She weighed 31 kg at diagnosis(95th centile in weight for age). Swabsamples obtained from the ulcer werepositive by PCR for IS2404, acid-alcohol-fast bacilli, and Mycobacterium ulceransculture on Lowenstein-Jensen cultureslopes. Patient was admitted, and antibi-otic combination therapy comprisingdaily intramuscular injection of 15 mg/kg of streptomycin and 10 mg/kg of oralrifampin was started together with woundcare and nutritional support.Two weeks into treatment, she wasnoted to have become breathless with theaccompaniment of fever and chills butwith no associated cough. Clinical exam-inations revealed the presence of pleuraleffusions bilaterally and pyrexia of37.9uC. Full blood counts revealed herwhite cell count had increased from 10.3x 103/L on admission to 20.8 x 103/L.An HIV antibody test was negative, andthe performance of a chest X-ray con-firmed the presence of bilateral pleuraleffusions (Figure 2). Diagnostic pleuralaspirate showed the effusion to be anexudate with an elevated protein con-centration of 82.5 g/l, pH= 7.5, andpredominantly neutrophils on cytopa-thology but no isolates on aerobic andanaerobic cultures. PCR on pleuralaspirate was positive for M. ulcerans butwas negative for tuberculosis—a differ-ential diagnosis. An aspirate of theeffusion was tested for the presence ofmycolactone using UPLC-mass spec-trometry, as described elsewhere [1],but the intact mycolactone A/B wasnot detected. The left pleural effusionwas drained with the aid of a chest tubeand by needle aspiration of the rightpleural effusion. She was put on 30 mgof oral prednisone twice daily for 2 weekswith resolution of the effusion within 2weeks of its appearance. However, theeffusion on the right side recurred(Figure 2D) and was managed success-fully by needle thoracocentesis. Uponcompletion of antimycobacterial antibi-otic therapy for 8 weeks, surgery wasperformed, comprising excision and skingrafting. The lesion healed graduallyover 48 weeks but resulted in a hyper-trophic scar over the manubrio-sternum.Parental informed consent was obtained.Case DiscussionThis case report is instructive inillustrating the successes and challengesassociated with Buruli ulcer managementin rural communities in endemic coun-tries and in highlighting a rare presenta-tion of paradoxical reaction of M. ulceransdisease. Combination antibiotic therapycomprising daily oral rifampin andintramuscular streptomycin for 8 weekshas demonstrated excellent efficacy inhealing all forms and categories of M.ulcerans disease, with surgery sometimesnecessary in large category III lesions(lesions .15 cm at its widest diameter)[2]. However, antibiotic therapy for M.ulcerans disease may be associated withparadoxical exacerbations or with theappearance of secondary lesions at dif-ferent sites, often referred to as aparadoxical reaction [3–6].Paradoxical reaction or exacerbationof mycobacterial infections during anti-biotic therapy is a well-characterisedphenomenon, and in M. ulcerans diseasea few case reports have been published[3–6]. However, to the best of ourknowledge, this is the first descriptionof pleural effusion in association withantibiotic-treatment-associated para-doxical reaction in M. ulcerans disease.In M. ulcerans disease, paradoxical reac-tions often are characterised by theoccurrence of inflammatory pus-filledlesions either close to the primary site ofthe lesion or sometimes at secondaryCitation: Sarfo FS, Thompson W, Phillips RO, Paintsil A, Abass MK, et al. (2014) A Severe Case of Buruli UlcerDisease with Pleural Effusions. PLoS Negl Trop Dis 8(6): e2868. doi:10.1371/journal.pntd.0002868Editor: Gerd Pluschke, Swiss Tropical and Public Health Institute, SwitzerlandPublished June 19, 2014Copyright:  2014 Sarfo et al. This is an open-access article distributed under the terms of the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.Funding: This study was funded by the European Community’s Seventh Framework Programme (FP7) undergrant agreement Nu 241500 http://www.burulivac.eu. The funders had no role in study design, data collectionand analysis, decision to publish, or preparation of the manuscript.Competing Interests: The authors have declared that no competing interests exist.* E-mail: stephensarfo78@gmail.comPLOS Neglected Tropical Diseases | www.plosntds.org 1 June 2014 | Volume 8 | Issue 6 | e2868sites distant from the primary lesions.These lesions either occur during orsome weeks after completion of antibi-otic therapy. The phenomenon, akin tothe immune reconstitution inflammato-ry syndrome amongst HIV patients onantiretroviral therapy, is thought to bedue to an exuberant reconstitution ofthe local immune response during thedemise of M. ulcerans bacilli under theinfluence of antibiotic therapy andmediated by immunostimulators [7]released from dying mycobacteria in amilieu of declining mycolactone con-centrations. This is evidenced histolog-ically by massive leucocyte infiltrationsof necrotic areas in surgically excisedparadoxical lesions in contrast to theacellular to scanty immune cell infil-trates observed in untreated M. ulcerans–infected skin lesions.Although M. ulcerans causes a pre-dominantly cutaneous infection, it mayoccasionally involve deeper structuressuch as the bone, causing osteomyelitis.Mycolactone has been shown to becytotoxic to a range of immune andnonimmune cells [8]. It is possible thatthe manifestation of bilateral pleuraleffusions in this patient who had anextensive oedematous lesion on thechest wall may signify a local destruc-tion and extension through the chest-wall muscles into the pleural cavities.Against this proposition is the absenceof clinically or radiologically demon-strable pneumothoraces. The mostprobable explanation, however, is thatM. ulcerans might have been carried intothe pleural cavity via the lymphatics toelicit a vigorous inflammatory responseonce mycolactone concentrations beganto decline under the influence of antibi-otic therapy. In murine studies, M.ulcerans is found to be present in localand regional lymph nodes at some stageduring infection [9].This patient improved on supportivetherapy comprising thoracocentesis, a 2-week course of prednisone, completion ofthe 8-week course of antibiotics, nutrition-al support, and surgical therapy includingdebridement and skin grafting, with herlesions healing without recurrence.Figure 1. An extensive category III oedematous lesion involving the anterior and posterior chest and neck regions, with two ulcers:one at the anterior triangle of the neck, measuring 6 cm x 8 cm, and another over the midsternal region of the chest, measuring3 cm x 4 cm.doi:10.1371/journal.pntd.0002868.g001PLOS Neglected Tropical Diseases | www.plosntds.org 2 June 2014 | Volume 8 | Issue 6 | e2868Figure 2. Chest radiographs of patient before and during antibiotic chemotherapy for M. ulcerans disease. (A) Chest X-ray taken beforeantibiotic therapy was started. (B) Chest X-ray taken 2 weeks after initiation of antibiotic therapy, showing bilateral pleural effusions. (C) Week 3 afterdrainage of pleural effusion. (D) Recurrence of pleural effusion on the right hemithorax at week 4.doi:10.1371/journal.pntd.0002868.g002Key Learning PointsN M. ulcerans disease of the chest wall may rarely be associated with exudativepleural effusions.N M. ulcerans cultures of pleural aspirates were negative, which is typical ofparadoxical reactions.N Management of pleural effusions due to paradoxical reactions should includethoracocentesis, steroid therapy, and management of ulcers along conventionallines.PLOS Neglected Tropical Diseases | www.plosntds.org 3 June 2014 | Volume 8 | Issue 6 | e2868References1. Sarfo FS, Converse PJ, Almeida DV, Zhang J,Robinson C, et al. (2013) Microbiological,histological, immunological and toxin responseto antibiotic treatment in the mouse model ofMycobacterium ulcerans disease. PLoS NeglTrop Dis 7: e2101.2. Sarfo FS, Phillips R, Asiedu K, Ampadu E, BobiN, et al. (2010) Clinical efficacy of combination ofrifampin and streptomycin for treatment ofMycobacterium ulcerans disease. Antimicrob AgentsChemother 54: 3678–3685.3. Ruf MT, Chauty A, Adeye A, Ardant MF,Koussemou H, et al. (2011) Secondary Buruliulcer skin lesions emerging several months aftercompletion of chemotherapy: paradoxical reac-tion or evidence for immune protection? PLoSNegl Trop Dis 5: e1252.4. O’Brien DP, Robson ME, Callan PP, McDonaldAH (2009) ‘‘Paradoxical’’ immune-mediated re-actions to Mycobacterium ulcerans during antibiotictreatment: a result of treatment success notfailure. Med J 191: 564–566.5. Nienhuis WA, Stienstra Y, Abass KM, Tuah W,Thompson WA, et al. (2012) Paradoxical re-sponses after start of antimicrobial treatment inMycobacterium ulcerans infection. Clin InfectDis. 54: 19–526.6. Beissner M, Piten E, Maman I, Symank D,Jansson M, et al. (2012) Spontaneous clearance ofa secondary Buruli ulcer lesion emerging tenmonths after completion of chemotherapy-a casereport from Togo. PLoS Negl Trop Dis 6: e1747.7. Schutte D, Pluschke G (2009) Immunosuppressionand treatment-associated inflammatory response inpatients with Mycobacterium ulcerans infection(Buruli ulcer). Expert Opin Biol Ther 9: 187–200.8. Demangel C, Stinear TP, Cole ST (2009) Buruliulcer: reductive evolution enhances pathogenicityof Mycobacterium ulcerans. Nat Rev Microbio 7:50–60.9. Martins TG, Gama JB, Fraga AG, Saraiva M,Silva MT, et al. (2012) Local and regional re-establishment of cellular immunity during cura-tive antibiotherapy of murine Mycobacterium ulcer-ans infection. PLoS One 7: e32740.PLOS Neglected Tropical Diseases | www.plosntds.org 4 June 2014 | Volume 8 | Issue 6 | e2868

Buruli ulcer: reductive evolution enhances pathogenicity of Mycobacterium ulcerans.

Clinical efficacy of combination of rifampin and streptomycin for treatment of Mycobacterium ulcerans disease.

Immunosuppression and treatment-associated inflammatory response in patients with Mycobacterium ulcerans infection (Buruli ulcer).

Local and regional reestablishment of cellular immunity during curative antibiotherapy of murine Mycobacterium ulcerans infection.

Microbiological, histological, immunological and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.

Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection. Clin Infect Dis.

Paradoxical’’ immune-mediated reactions to Mycobacterium ulcerans during antibiotic treatment: a result of treatment success not failure.

Secondary Buruli ulcer skin lesions emerging several months after completion of chemotherapy: paradoxical reaction or evidence for immune protection? PLoS Negl Trop Dis 5:

Spontaneous clearance of a secondary Buruli ulcer lesion emerging ten months after completion of chemotherapy-a case report from Togo.

A severe case of buruli ulcer disease with pleural effusions.

A severe case of buruli ulcer disease with pleural effusions.

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