• View in gallery

    Patient DR at admission (May 18, 2007), with bifocal lesions on (A, B) the right foot and (C, D) the left hand. This figure appears in color at www.ajtmh.org.

  • View in gallery

    Histopathologic appearance of lesions at admission. Type of specimen: skin (epidermis, dermis, hypodermis). Lesions: psoriasiform hyperplasia of the skin (A); coagulative necrosis (B, >>) of the hypodermis with calcification foci (C, +) and inflammatory infiltration of mild to moderate intensity (neutrophils, lymphocytes) (D, ***). Images of vasculitis (D, = >). Diagnosis: consistent with BU. Hematoxylin and eosin staining (HE). This figure appears in color at www.ajtmh.org.

  • View in gallery

    Histopathologic appearance of lesions after 4 weeks of S+R therapy (June 2007). Ziehl-Neelsen (ZN) staining showing coagulative necrosis, steatonecrosis, many clusters of bacilli in the interlobular wall (A) and few clusters of bacilli in the coagulative necrosis area (B). Magnifications: A and B: ZN ×100. This figure appears in color at www.ajtmh.org.

  • View in gallery

    Patient DR dissemination steps after the beginning of S+R therapy: July 2007 (W10): (A) first dissemination with swelling of the left elbow and (B) right hand; August 2007 (W12): (C) second dissemination with swelling of the left foot and (D) a plaque with a small ulcer on the right elbow; December 2007 (M7) and January 2008 (M8): (E) fourth and fifth disseminations with swelling of the right wrist and (F) the right foot; March 2008 (M10): (G) sixth dissemination with ulcer on the right knee; January 2009 (M20): (H) seventh dissemination with swelling on the lateral aspect of the right leg. This figure appears in color at www.ajtmh.org.

  • 1.

    Lagarrigue V, Portaels F, Meyers WM, Aguiar J, 2000. Buruli ulcer: risk of bone involvement! A propos of 33 cases observed in Benin. Méd Trop 60: 262266

    • Search Google Scholar
    • Export Citation
  • 2.

    Portaels F, Zinsou C, Aguiar J, Debacker M, de Biurrun E, Guédénon A, Josse R, Lagarrigue V, Silva MT, Steunou C, Meyers WM, 2003. Les atteintes osseuses de l'ulcère de Buruli: à propos de 73 cas. Bull Seances Acad R Sci Outre Mer 49: 161190.

    • Search Google Scholar
    • Export Citation
  • 3.

    World Health Organization, 2001. Buruli ulcer. Diagnosis of Mycobacterium ulcerans disease. Portaels F, Johnson P, Meyers WM, eds. A Manual for Health Care Providers. Geneva: WHO/CDS/CPE/GBUI/2001.4.

    • Search Google Scholar
    • Export Citation
  • 4.

    Walsh DS, Portaels F, Meyers WM, 2008. Buruli ulcer (Mycobacterium ulcerans infection). Trans R Soc Trop Med Hyg 102: 969978.

  • 5.

    Debacker M, Aguiar J, Steunou C, Zinsou C, Meyers WM, Guédénon A, Scott JT, Dramaix M, Portaels F, 2004. Mycobacterium ulcerans disease (Buruli ulcer) in rural hospital, southern Benin, 1997–2001. Emerg Infect Dis 10: 13911398.

    • Search Google Scholar
    • Export Citation
  • 6.

    Portaels F, Silva MT, Meyers WM, 2009. Buruli ulcer. Clin Dermatol 27: 291305.

  • 7.

    Johnson RC, Ifebe D, Hans-Moevi A, Kestens L, Houessou R, Guédénon A, Meyers WM, Portaels F, 2002. Disseminated Mycobacterium ulcerans disease in an HIV-positive patient: a case study. AIDS 16: 17041705.

    • Search Google Scholar
    • Export Citation
  • 8.

    Toll A, Gallardo F, Ferran M, Gilaberte M, Iglesias M, Gimeno JL, Rondini S, Pujol RM, 2005. Aggressive multifocal Buruli ulcer with associated osteomyelitis in an HIV-positive patient. Clin Exp Dermatol 30: 649651.

    • Search Google Scholar
    • Export Citation
  • 9.

    Ouattara D, Meningaud JP, Saliba F, 2002. Multifocal forms of Buruli ulcer: clinical aspects and management difficulties in 11 cases. Bull Soc Pathol Exot 95: 287291

    • Search Google Scholar
    • Export Citation
  • 10.

    Eddyani M, Fraga AG, Schmitt F, Uwizeye C, Fissette K, Johnson C, Aguiar J, Sopoh G, Barogui Y, Meyers WM, Pedrosa J, Portaels F, 2009. Fine needle aspiration, an efficient sampling technique for bacteriological diagnosis of non ulcerative Buruli ulcer. J Clin Microbiol 47: 17001704.

    • Search Google Scholar
    • Export Citation
  • 11.

    World Health Organization, 2004. Provisional guidance on the role of specific antibiotics in the management of Mycobacterium ulcerans disease (Buruli ulcer). Geneve: WHO/CDS/CPE/GBUI.10.

    • Search Google Scholar
    • Export Citation
  • 12.

    World Health Organization, 2008. Buruli ulcer: progress report, 2004–2008. Wkly Epidemiol Rec 83: 145146. Available at: http://whqlibdoc.who.int/hq/2001/WHO_CDS_CPE_GBUI_2001.3.pdf. Accessed April 4, 2008.

    • Search Google Scholar
    • Export Citation
  • 13.

    Portaels F, Johnson C, Aguiar J, Meyers WM, Debacker M, 2008. Etude de 106 cas d'ulcères de Buruli avec atteintes osseuses traités à Zagnanado, Bénin. Bull de l'ALLF 23: 4850.

    • Search Google Scholar
    • Export Citation
  • 14.

    Pszolla N, Sarkar MR, Strecker W, Kern P, Kinzl L, Meyers WM, Portaels F, 2003. Buruli ulcer: a systemic disease. Clin Infect Dis 37: 7882.

  • 15.

    Silva MT, Portaels F, Pedrosa JR, 2009. Pathogenetic mechanisms of the intracellular parasite Mycobacterium ulcerans leading to Buruli ulcer. Lancet Infect Dis 9: 699710.

    • Search Google Scholar
    • Export Citation
  • 16.

    Guarner J, Bartlett J, Whitney EAS, Raghunathan PL, Stienstra Y, Asamoa K, Etuaful S, Klutse E, Quarshie E, van der Werf TS, van der Graaf WT, King CH, Ashford DA, 2003. Histopathologic features of Mycobacterium ulcerans infection. Emerg Infect Dis 9: 651656.

    • Search Google Scholar
    • Export Citation
  • 17.

    Limbos P, Bretey J, Jadin J, Brutsaert P, 1961. Sur un cas d'abcès à Mycobacterium fortuitum. Ann Soc Belg Med Trop 2: 127132.

  • 18.

    Wang CT, Sun JS, Hou SM, 2000. Mycobacterial infection of the upper extremities. J Formos Med Assoc 99: 710715.

  • 19.

    Mauvieux L, 2005/2006. Les hyperéosinophilies. Université Louis Pasteur – Faculté de Médecine - 2005/2006 - DCEM3 - Module 17 - Maladies du Sang et Transfusion- Item 311. Available at: http://www-ulpmed.u-strasbg.fr/medecine/cours_en_ligne/e_cours/module_17/item_311.pdf. Accessed June 4, 2010.

    • Search Google Scholar
    • Export Citation
  • 20.

    Schütte D, Pluschke G, 2009. Immunosuppression and treatment-associated inflammatory response in patients with Mycobacterium ulcerans infection (Buruli ulcer). Expert Opin Biol Ther 9: 187200.

    • Search Google Scholar
    • Export Citation
  • 21.

    Schütte D, Um-Boock A, Mensah-Quainoo E, Itin P, Schmid P, Pluschke G, 2007. Development of highly organized lymphoid structures in Buruli ulcer lesions after treatment with rifampicin and streptomycin. PLoS Negl Trop Dis 1: e2.

    • Search Google Scholar
    • Export Citation
  • 22.

    O'Brien DP, Robson ME, Callan PP, McDonald AH, 2009. “Paradoxical” immune-mediated reactions to Mycobacterium ulcerans during antibiotic treatment: a result of treatment success, not failure. Med J Aust 191: 564566.

    • Search Google Scholar
    • Export Citation
  • 23.

    Kestens L, Seddiki N, Bohjanen PR, 2009. Immunopathogenesis of immune reconstitution disease in HIV patients responding to antiretroviral therapy. Curr Opin HIV AIDS 3: 419424.

    • Search Google Scholar
    • Export Citation
  • 24.

    Lawn DS, Lockwood DN, 2007. Leprosy after starting antiretroviral treatment: an increasingly reported clinical problem but not a serious public health risk. BMJ 334: 217218.

    • Search Google Scholar
    • Export Citation
  • 25.

    Corti M, Villafañe MF, Ambroggi M, Sawicki M, Gancedo E, 2007. Soft tissue abscess and lymphadenitis due to Mycobacterium avium complex as an expression of immune reconstitution inflammatory syndrome after a second scheme of highly active antiretroviral therapy: case report. Rev Inst Med Trop Sao Paulo 49: 267270.

    • Search Google Scholar
    • Export Citation
  • 26.

    Singal A, Mehta S, Pandhi D, 2006. Immune reconstitution inflammatory syndrome in an HIV seropositive leprosy patient. Lepr Rev 77: 7680.

  • 27.

    Fock RA, Vinolo MA, Crisma AR, Nakajima K, Rogero MM, Borelli P, 2008. Protein-energy malnutrition modifies the production of interleukin-10 in response to lipopolysaccharide (LPS) in a murine model. J Nutr Sci Vitaminol (Tokyo) 54: 371377.

    • Search Google Scholar
    • Export Citation
  • 28.

    Rodriguez L, Gonzalez C, Flores L, Jimenez-Zamudio L, Graniel J, Ortiz R, 2005. Assessment by flow cytometry of cytokine production in malnourished children. Clin Diagn Lab Immunol 12: 502507.

    • Search Google Scholar
    • Export Citation
  • 29.

    Schaible UE, Kaufmann SH, 2007. Malnutrition and infection: complex mechanisms and global impacts. PLoS Med 4: e115.

  • 30.

    Funada H, Machi T, Matsuda T, 1991. Disseminated mycobacteriosis in patients with severe hematologic disorders. Kansenshogaku Zasshi 65: 12971303.

    • Search Google Scholar
    • Export Citation
  • 31.

    Skinsnes LK, Higa LH, 1976. The role of protein malnutrition in the pathogenesis of ulcerative “Lazarine” leprosy. Int J Lepr Other Mycobact Dis 44: 346358.

    • Search Google Scholar
    • Export Citation
  • 32.

    Stienstra Y, Van Der Werf TS, Oosterom E, Nolte IM, van der Graaf WT, Etuaful S, Raghunathan PL, Whitney EA, Ampadu EO, Asamoa K, Klutse EY, te Meerman GJ, Tappero JW, Ashford DA, van der Steege G, 2006. Susceptibility to Buruli ulcer is associated with the SLC11A1 (NRAMP1) D543N polymorphism. Genes Immun 7: 185189.

    • Search Google Scholar
    • Export Citation
  • 33.

    Mulder AA, Boerma RP, Barogui Y, Zinsou C, Johnson RC, Gbovi J, van der Werf TS, Stienstra Y, 2008. Healthcare seeking behaviour for Buruli ulcer in Benin: a model to capture therapy choice of patients and healthy community members. Trans R Soc Trop Med Hyg 102: 912920.

    • Search Google Scholar
    • Export Citation
  • 34.

    Kibadi K, Stragier P, Muyembe-Tamfum JJ, Pedrosa J, Portaels F, 2008. Follow-up of the first case of Mycobacterium ulcerans infection documented by PCR, genotyping and culture in the Republic of Congo-Brazzaville]. Méd Trop 68: 137143.

    • Search Google Scholar
    • Export Citation
 
 
 
 

 

 
 

 

 

 

 

 

 

Severe Multifocal Form of Buruli Ulcer after Streptomycin and Rifampin Treatment: Comments on Possible Dissemination Mechanisms

View More View Less
  • Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) d'Allada, Bénin; Unité d'Anatomie Pathologique, Faculté de Médecine, université de Parakou, Parakou, Bénin; Centre de Dépistage et de Traitement de l'Ulcère de Buruli de Lalo, Bénin; Laboratoire de Référence des Mycobactéries (LRM), PNT, Cotonou, Bénin; Programme National de Lutte contre la Lèpre et l'Ulcère de Buruli (PNLLUB), Cotonou, Bénin; Immunology Unit, Institute of Tropical Medicine (ITM), Antwerpen, Belgium; Mycobateriology Unit, Institute of Tropical Medicine (ITM), Antwerpen, Belgium

Buruli ulcer (BU), a disease caused by Mycobacterium ulcerans, leads to the destruction of skin and sometimes bone. Here, we report a case of severe multifocal BU with osteomyelitis in a 6-year-old human immunodeficiency virus (HIV)-negative boy. Such disseminated forms are poorly documented and generally occur in patients with HIV co-infection. The advent of antibiotic treatment with streptomycin (S) and rifampin (R) raised hope that these multifocal BU cases could be reduced. The present case raises two relevant points about multifocal BU: the mechanism of dissemination that leads to the development of multiple foci and the difficulties of treatment of multifocal forms of BU. Biochemical (hypoproteinemia), hematological (anemia), clinical (traditional treatment), and genetic factors are discussed as possible risk factors for dissemination.

Introduction

Buruli ulcer (BU), a disease caused by Mycobacterium ulcerans, leads to the destruction of skin and sometimes bone.1,2 Buruli ulcer is rarely fatal, but poorly treated cases often result in contracture deformities, which are the main complication of BU. The disease presents in two main active clinical forms: non-ulcerative (papule, nodule, plaque, and edema) and ulcerative.3 Other forms have also been described, namely the osteomyelitis and disseminated (or multifocal) forms.46

The multifocal forms, though rarely described in the literature, have been associated with osteomyelitis and human immunodeficiency virus (HIV) coinfection.1,2,59 However, the dissemination process behind these forms is not fully understood. Here, we present the case of a young boy who was admitted to the hospital with a bifocal form of BU that disseminated during treatment, generating several new foci.

Case Report

A 6-year-old boy (DR) from Adjohoun (Oueme department, south Benin) was admitted to the BU treatment center of Allada (Atlantique department, south Benin) on May 18, 2007, 3 months after the appearance of the first lesion (according to his parents). His medical history included Bacille Calmet-Guerin (BCG) immunization and two cousins who had been diagnosed with BU in the past, one of whom had died of the disseminated form 2 years prior. DR's condition at admission was very poor, with moderate to severe malnutrition and the following Z scores: height for age = −2.90, weight for height = − 1.67, and weight for age = −2.87 (normal ranges = −1 to +1). He presented with two different clinical lesions (mixed form) at two different sites (bifocal form), with plaques and ulcers on the right foot and the left hand (Figure 1). According to his parents, the initial lesion was edema of a finger (left hand) that evolved into a plaque after a few days. He was treated first with herbs by a traditional healer in his village, but 2 weeks later, a new edematous lesion appeared on the right toe, and this lesion also evolved to a plaque that covered the whole foot. No other lesions were detected at the time of his admission. Microbiological examinations of biopsies and fine needle aspirations (FNA) were performed, as previously described.3,10 At admission, IS2404 polymerase chain reaction (PCR) and direct smear examination (DSE) after Ziehl-Neelsen (ZN) stain were positive, but cultures on Löwenstein-Jensen media were negative. Histopathology revealed lesions consistent with BU (Figures 2 and 3). All of these epidemiological, clinical, and microbiological features confirmed a category 3 BU case, according to World Health Organization (WHO) definitions.3,11,12 In addition, radiography revealed focal osteomyelitis under the two lesions. Other biological examinations showed moderate anemia (hemoglobin = 11 g/dL; normal range [NR] = 12–16 g/dL), leukocytosis (white blood cells [WBC] = 35,000/dL; NR = 6000–8000/dL), and eosinophilia (8%, NR = 0–2%). He also had hypoproteinemia (protein rate = 66.5 g/dL; NR = 70–80 g/dL). The human immunodeficiency virus (HIV) serology was negative and creatinine, transaminases, and blood sugar levels were normal.

Figure 1.
Figure 1.

Patient DR at admission (May 18, 2007), with bifocal lesions on (A, B) the right foot and (C, D) the left hand. This figure appears in color at www.ajtmh.org.

Citation: The American Society of Tropical Medicine and Hygiene 83, 2; 10.4269/ajtmh.2010.09-0617

Figure 2.
Figure 2.

Histopathologic appearance of lesions at admission. Type of specimen: skin (epidermis, dermis, hypodermis). Lesions: psoriasiform hyperplasia of the skin (A); coagulative necrosis (B, >>) of the hypodermis with calcification foci (C, +) and inflammatory infiltration of mild to moderate intensity (neutrophils, lymphocytes) (D, ***). Images of vasculitis (D, = >). Diagnosis: consistent with BU. Hematoxylin and eosin staining (HE). This figure appears in color at www.ajtmh.org.

Citation: The American Society of Tropical Medicine and Hygiene 83, 2; 10.4269/ajtmh.2010.09-0617

Figure 3.
Figure 3.

Histopathologic appearance of lesions after 4 weeks of S+R therapy (June 2007). Ziehl-Neelsen (ZN) staining showing coagulative necrosis, steatonecrosis, many clusters of bacilli in the interlobular wall (A) and few clusters of bacilli in the coagulative necrosis area (B). Magnifications: A and B: ZN ×100. This figure appears in color at www.ajtmh.org.

Citation: The American Society of Tropical Medicine and Hygiene 83, 2; 10.4269/ajtmh.2010.09-0617

Four days after admission, on May 22, 2007, streptomycin (S) and rifampin (R) therapy (S+R) was started according to WHO protocol.11 An assessment was conducted every 2 weeks (measurement of lesions, photography, and biopsy when possible). Because the clinical evolution of the lesions after 4 weeks was unfavorable (deterioration of the lesions and worsening of the patient's general condition), surgery was performed (excision and amputation of two fingers), and the patient completed 4 more weeks of S+R treatment.

Even though treatment compliance was excellent during the 8 weeks of S+R therapy (56 doses administered over 56 days), DR developed several episodes of dissemination. The various clinical features and evolution after completion of S+R therapy are summarized in Table 1 and illustrated in Figure 4A–H.

Table 1

Chronology of clinical features, dissemination episodes of the patient, and summary of the microbiological and histopathological results

Date (W no. or M no. after the beginning of S+R therapy)Description of lesionIllustrationDSEPCRHistopathologySurgery date (act*)
May 2007 Start S+R therapy• Admission to hospitalPositivePositiveConsistent with BU
• Plaque + ulcer + bone lesion on the right footFigure 1A and B
• Plaque + ulcers + bone lesion on the left handFigure 1C and D
June 2007 (W4)• Worsening of the initial lesions (plaque + ulcer + bone lesion on the right foot and the left hand)PositiveNegativeConsistent with BUJune 20, 2007 (excision and amputation of a toe and two fingers)
June 30, 2007 (amputation of the left hand)
July 2007 (W8)• End of S+R therapy
July 2007 (W10)• 1st disseminationPositivePositiveAugust 2, 2007 (excision and bone surgery)
• Swelling + bone lesion on the left elbowFigure 4A
• Swelling + bone lesion on the right middle fingerFigure 4B
August 2007 (W12)• 2nd disseminationNegativePositiveInflammatory infiltrate, not specific to BUAugust 17, 2007 (excision)
• Swelling on the left footFigure 4C
• Plaque + small ulcer and bone lesion on the right elbowFigure 4DPositivePositiveAugust 27, 2007 (excision and bone surgery)
October 2007 (M5)• 3rd dissemination: plaque + ulcer + bone lesion on the left elbowNegativePositiveOctober 18, 2007 (excision)
November 15, 2007 (bone surgery)
December 2007 (M7)• 4th dissemination: swelling on the right wristFigure 4EPositiveNot doneVasculitis and vascular thrombosisJanuary 31, 2008 (excision)
January 2008 (M8)• 5th dissemination: swelling + bone lesion on the left footFigure 4FPositivePositiveFebruary 28, 2008 (excision and bone surgery)
March 2008 (M10)• 6th dissemination: ulcer (less than 5 cm in diameter) + bone lesion on the right kneeFigure 4GPositiveNot doneMay 5, 2008 (bone surgery)
November 2008 (M18)• End of hospitalization
January 2009 (M20)• 7th dissemination: swelling on the lateral aspect of the right legFigure 4H
Figure 4.
Figure 4.

Patient DR dissemination steps after the beginning of S+R therapy: July 2007 (W10): (A) first dissemination with swelling of the left elbow and (B) right hand; August 2007 (W12): (C) second dissemination with swelling of the left foot and (D) a plaque with a small ulcer on the right elbow; December 2007 (M7) and January 2008 (M8): (E) fourth and fifth disseminations with swelling of the right wrist and (F) the right foot; March 2008 (M10): (G) sixth dissemination with ulcer on the right knee; January 2009 (M20): (H) seventh dissemination with swelling on the lateral aspect of the right leg. This figure appears in color at www.ajtmh.org.

Citation: The American Society of Tropical Medicine and Hygiene 83, 2; 10.4269/ajtmh.2010.09-0617

We noted that the emergence of each new disseminated lesion was always preceded by an episode of fever over 39°C and a high white blood cell (WBC) count, as well as eosinophilia ranging between 0% and 10%. Anemia was also present, with a hemoglobin concentration ranging between 6.2 and 10.1 g/dL (Table 2). Fine needle aspiration (FNA) and biopsies from these new lesions were DSE or PCR positive, but cultures remained negative. Histopathologic examination revealed coagulative necrosis, eosinophilic infiltration, neutrophil-containing inflammatory infiltration, vasculitis, and vascular thrombosis. The microbiologic and histopathologic results are presented in Table 1. Stool examinations for parasites, including cysts and eggs, were negative.

Table 2

Summary of hematology and biochemical results*

Period after beginning of S+R therapyHb (g/dL)Htc (%)WBC (no./dL)PN (%)Eo (%)L (%)M (%)Proteinemia (g/L)Fraction Albumin/globulinAlbumin (g/L)Alpha 1 (g/L)Alpha 2 (g/L)Beta 1 (g/L)Beta 2 (g/L)Gamma (g/L)
Normal values12–1637–436000–800060–65230-355–870–8042–500.7–25–92–64–82–12
W110.1↓3222,700↑5010↑301066.5↓0.7328.0↓5.7↑9.65.94.313.0
W48.56↓2313,900↑74020655.0↓0.8224.8↓4.2↑8.25.82.99.1
W106.2↓2219,400↑686280104.10.7042.95.9↑13.8↑9.7↑3.028.8↑
W127.64↓2211,000↑562420
M58.63↓2815,300↑564400
M107.82↓2414,100↑448462

↑ = increase of the value compared with the normal range; ↓ = decrease of the value compared with the normal range; Hb = hemoglobin; Htc = hematocrit; WBC = white blood cells; PN = polynuclear neutrophils; Eo = eosinophils; L = lymphocytes.

All new lesions were excised, and the skin was grafted as soon as possible. During surgery, bone involvement was detected under each new lesion. Thus, bone surgery was also performed in addition to the excision of infected soft tissue (Table 1). During fever episodes, large spectrum antibiotics were administered several times without success. These antibiotics included ceftriaxon (50 mg/kg/day) or a combined therapy of amoxicillin (100 mg/kg/day), metronidazole (30 mg/kg/day), and gentamicin (3 mg/kg/day) for at least 10 days.

A blood sample was collected in April 2009 to study the immune status of the patient. The results indicated that the lymphocyte differential count (T, B, and natural killer [NK] cells) was normal for a child of his age. The young patient had 2,587 CD4+ T cells (45%) per µL and 1,438 CD8+ T cells per µL (25%), as well as a normal CD4+:CD8+ ratio of 1.8. The number of NK cells per µL was 512 (8.9%), and the number of B cells per µL was 978 (17%). No excessive T cell activation was observed; 8.4% of the CD4+ T cells and 0.6% of the CD8+ T cells expressed the cell membrane activation marker CD38 on their memory subsets (CD45RO+ cells), indicating a normal activation state.

All lesions healed, and the patient was cured after 18 months of hospitalization and 15 surgical interventions but with severe sequelae (amputation of the left hand and the second right toe; functional limitation of elbows, the right wrist, the right knee, and both ankles).

Discussion

Two relevant aspects of this case should be considered: the mechanism of dissemination leading to the development of multiple foci and the difficulties of treatment of the multifocal forms of BU. The rare published cases of disseminated forms of BU are often associated with bone involvement1,2,5,8,9 and/or HIV co-infection.7,8 The first large series of BU with laboratory-confirmed bone involvement focused on 73 cases from 18 months to 45 years of age with a median age of 14.5 years.2 Thirty out of the 73 selected cases had a multifocal form at admission. Some of those patients continued to develop new lesions during hospitalization or after cure of all initial lesions. Nine of them were tested for HIV, of whom four (44.4%) were positive, confirming the association between the BU multifocal form, bone involvement, and HIV co-infection. Most BU osteomyelitis and disseminated lesions are localized to limbs, at distal joints, and on small bones.1,2,6,9 The number of foci typically range between two and seven,1,9 and our case is in accordance with these observations. This case also shows that apparently small or non-ulcerated lesions may hide bone involvement. Thus, practitioners should consider obtaining radiographic images in the presence of known risk factors for osteomyelitis, such as multifocal BU or HIV co-infection.13,14

No previous publication has addressed the general clinical symptoms or biochemical and hematological parameters in disseminated BU cases. In this case, and in many other cases treated in the BU treatment centers of Allada and Zagnanado in Benin (Aguiar J, personal communication), fever and an increase in WBCs occurred before the development of each new lesion, despite the administration of large-spectrum antibiotics, even in patients treated with surgery alone. Secondary infections or other bacteria sepsis may explain these phenomena. Unfortunately, blood cultures are not available in our setting. However, the lack of response to antibiotics allows us to discard these hypotheses (secondary infections or other bacteria sepsis) and suggest a probable bacteremia with extracellular or intraphagocytic M. ulcerans. Mycobacterium ulcerans is known to be present within phagocytes in BU lesions.15,16 Accordingly, the presence of the bacteria in the new lesions was confirmed by the positive DSE or PCR results (Table 1) and the presence of acid-fast bacilli (AFB) on histopathologic slides. In addition, the distributions of these AFB indicated that the lesions were new, active ones. Indeed, numerous extracellular AFB were seen in the interlobular wall in the subcutaneous tissue (Figure 3A) and very few in the areas of coagulative necrosis (Figure 3B). A high eosinophil count during BU disease has never been described. It is unlikely that eosinophilia, both in the blood and in tissue, is related to intestinal parasitic infection, as the stool examinations were negative. A skin parasitic co-infection could be speculated here but cannot be proved. However, the presence of eosinophilia in mycobacterial diseases has been reported.1719 The high eosinophil count could also be linked to the antibiotics received by the patient (streptomycin and amoxicillin) or a possible immunoglobulin E (IgE)-dependent hypersensitivity.19

The emergence of new lesions could be linked to an excessive specific immune response. The histopathologic results revealed neutrophil-containing inflammatory infiltrates, vasculitis and vascular thrombosis, indicating that there was an intensive inflammatory response. Several reports have described a similar excessive immune response following effective antimycobacterial therapy.2022 This phenomenon, called “paradoxical reaction”22 or “immune reconstitution inflammatory syndrome (IRIS),” has also been described in patients with HIV who are coinfected with other mycobacteria, such as Mycobacterium tuberculosis or Mycobacterium leprae.23,24 Although our patient was HIV-negative, the IRIS is highly supported by the clinical characteristics (fever, swelling, or abscess) previously described,20,2426 the increase in the WBC count, the alpha-1, alpha-2, and gamma globulin values (Table 2), and the histopathologic results. Because of technical constraints, the immune status of this patient was not extensively assessed at admission. Even though he was HIV-negative and the limited immunological evaluation did not reveal immunodeficiency in April 2009, other immunosuppressive factors were observed at admission, namely hypoproteinemia. Fock and others27 and Rodriguez and others28 showed that protein-energy malnutrition increases the production of immunosuppressive interleukin in response to lipopolysaccharide (LPS) stimulation. This impairs immune responses, increasing susceptibility to infections.29 Similarly, other authors have described disseminated tuberculosis in patients with weight loss,30 or disseminated leprosy in rats submitted to a protein-free diet.31 In our case, infected tissues were removed surgically, which contributed, in addition to protein supplements, to the improvement of the general status of the patient. Subsequently, at the time of the first dissemination, protein levels normalized (Table 2). Therefore, it is possible that the IRIS in this BU case was simply caused by the correction of immunosuppressive factors, namely hypoproteinemia.

Anemia could also be a factor that promotes dissemination. Our patient had moderate anemia at admission but severe anemia concomitant with each new lesion (Table 2). Pszolla and others14 suggested that low tissue oxygen levels could promote the hematogenous spreading of M. ulcerans. This low tissue oxygenation could have several etiologies, including anemia and vascular thrombosis. The role of hypoproteinemia and anemia as possible risk factors in the dissemination of BU lesions may have an important impact on treatment. Clinicians might consider anemia correction and protein supplementation as adjuvant treatment of BU.

Stienstra and others32 have demonstrated the role of the SLC11A1 (NRAMP1) gene in susceptibility to BU, as in tuberculosis and leprosy. Our patient had two cases of BU in his family history, suggesting the possible involvement of genetic factors. However, additional studies are necessary to explore the possible link between genetic factors and the occurrence of severe forms of BU. Other factors that could be explored are the virulence of the bacteria and the herbal treatment sought by most patients in Benin (including DR) as a first treatment choice before presenting to a hospital.33

Before 2004, BU treatment consisted of wide excision of the affected and healthy surrounding tissue.12 Thus, the number of surgical interventions that patients with disseminated BU endured was quite significant (up to 32).2 The current WHO protocol combines S+R, surgery, and physiotherapy, depending on the category of the lesion.11,12 With this new protocol, the hope was to reduce the risk of dissemination for category 3 lesions. Despite strict adherence to these recommendations, in our case, new lesions still appeared 20 months after initial therapy. Such disseminated lesions during antimycobacterial treatment associated with surgery have been described elsewhere13,14,34 and emphasize the difficulties of treatment of such cases even with the combination of antibiotherapy and surgery. Because of the comprehensive clinical, biological, and treatment data available in our case, several factors that may contribute to the observed dissemination have been highlighted. However, many questions remain to be clarified concerning the mechanisms involved in the dissemination of M. ulcerans in BU patients and the occurrence of paradoxical reactions during antibiotic treatment.

Acknowledgments:

We are grateful to the parents of the patient DR for giving their consent for publication of the history of their child; all of the staff of CDTUB Allada and partners who support the PNLLUB and the CDTUB Allada, in particular the Government of Benin; Burulico Project (European Union), project INCO-CT-2005-051476; Damien Action, Brussels, Belgium; Directorate General for Development and Cooperation (DGDC), Brussels, Belgium; Raoul Follereau Foundation of Luxembourg; World Health Organization (WHO), Geneva, Switzerland. We thank M.T. Silva and F. Paasch for critical review of this manuscript.

  • 1.

    Lagarrigue V, Portaels F, Meyers WM, Aguiar J, 2000. Buruli ulcer: risk of bone involvement! A propos of 33 cases observed in Benin. Méd Trop 60: 262266

    • Search Google Scholar
    • Export Citation
  • 2.

    Portaels F, Zinsou C, Aguiar J, Debacker M, de Biurrun E, Guédénon A, Josse R, Lagarrigue V, Silva MT, Steunou C, Meyers WM, 2003. Les atteintes osseuses de l'ulcère de Buruli: à propos de 73 cas. Bull Seances Acad R Sci Outre Mer 49: 161190.

    • Search Google Scholar
    • Export Citation
  • 3.

    World Health Organization, 2001. Buruli ulcer. Diagnosis of Mycobacterium ulcerans disease. Portaels F, Johnson P, Meyers WM, eds. A Manual for Health Care Providers. Geneva: WHO/CDS/CPE/GBUI/2001.4.

    • Search Google Scholar
    • Export Citation
  • 4.

    Walsh DS, Portaels F, Meyers WM, 2008. Buruli ulcer (Mycobacterium ulcerans infection). Trans R Soc Trop Med Hyg 102: 969978.

  • 5.

    Debacker M, Aguiar J, Steunou C, Zinsou C, Meyers WM, Guédénon A, Scott JT, Dramaix M, Portaels F, 2004. Mycobacterium ulcerans disease (Buruli ulcer) in rural hospital, southern Benin, 1997–2001. Emerg Infect Dis 10: 13911398.

    • Search Google Scholar
    • Export Citation
  • 6.

    Portaels F, Silva MT, Meyers WM, 2009. Buruli ulcer. Clin Dermatol 27: 291305.

  • 7.

    Johnson RC, Ifebe D, Hans-Moevi A, Kestens L, Houessou R, Guédénon A, Meyers WM, Portaels F, 2002. Disseminated Mycobacterium ulcerans disease in an HIV-positive patient: a case study. AIDS 16: 17041705.

    • Search Google Scholar
    • Export Citation
  • 8.

    Toll A, Gallardo F, Ferran M, Gilaberte M, Iglesias M, Gimeno JL, Rondini S, Pujol RM, 2005. Aggressive multifocal Buruli ulcer with associated osteomyelitis in an HIV-positive patient. Clin Exp Dermatol 30: 649651.

    • Search Google Scholar
    • Export Citation
  • 9.

    Ouattara D, Meningaud JP, Saliba F, 2002. Multifocal forms of Buruli ulcer: clinical aspects and management difficulties in 11 cases. Bull Soc Pathol Exot 95: 287291

    • Search Google Scholar
    • Export Citation
  • 10.

    Eddyani M, Fraga AG, Schmitt F, Uwizeye C, Fissette K, Johnson C, Aguiar J, Sopoh G, Barogui Y, Meyers WM, Pedrosa J, Portaels F, 2009. Fine needle aspiration, an efficient sampling technique for bacteriological diagnosis of non ulcerative Buruli ulcer. J Clin Microbiol 47: 17001704.

    • Search Google Scholar
    • Export Citation
  • 11.

    World Health Organization, 2004. Provisional guidance on the role of specific antibiotics in the management of Mycobacterium ulcerans disease (Buruli ulcer). Geneve: WHO/CDS/CPE/GBUI.10.

    • Search Google Scholar
    • Export Citation
  • 12.

    World Health Organization, 2008. Buruli ulcer: progress report, 2004–2008. Wkly Epidemiol Rec 83: 145146. Available at: http://whqlibdoc.who.int/hq/2001/WHO_CDS_CPE_GBUI_2001.3.pdf. Accessed April 4, 2008.

    • Search Google Scholar
    • Export Citation
  • 13.

    Portaels F, Johnson C, Aguiar J, Meyers WM, Debacker M, 2008. Etude de 106 cas d'ulcères de Buruli avec atteintes osseuses traités à Zagnanado, Bénin. Bull de l'ALLF 23: 4850.

    • Search Google Scholar
    • Export Citation
  • 14.

    Pszolla N, Sarkar MR, Strecker W, Kern P, Kinzl L, Meyers WM, Portaels F, 2003. Buruli ulcer: a systemic disease. Clin Infect Dis 37: 7882.

  • 15.

    Silva MT, Portaels F, Pedrosa JR, 2009. Pathogenetic mechanisms of the intracellular parasite Mycobacterium ulcerans leading to Buruli ulcer. Lancet Infect Dis 9: 699710.

    • Search Google Scholar
    • Export Citation
  • 16.

    Guarner J, Bartlett J, Whitney EAS, Raghunathan PL, Stienstra Y, Asamoa K, Etuaful S, Klutse E, Quarshie E, van der Werf TS, van der Graaf WT, King CH, Ashford DA, 2003. Histopathologic features of Mycobacterium ulcerans infection. Emerg Infect Dis 9: 651656.

    • Search Google Scholar
    • Export Citation
  • 17.

    Limbos P, Bretey J, Jadin J, Brutsaert P, 1961. Sur un cas d'abcès à Mycobacterium fortuitum. Ann Soc Belg Med Trop 2: 127132.

  • 18.

    Wang CT, Sun JS, Hou SM, 2000. Mycobacterial infection of the upper extremities. J Formos Med Assoc 99: 710715.

  • 19.

    Mauvieux L, 2005/2006. Les hyperéosinophilies. Université Louis Pasteur – Faculté de Médecine - 2005/2006 - DCEM3 - Module 17 - Maladies du Sang et Transfusion- Item 311. Available at: http://www-ulpmed.u-strasbg.fr/medecine/cours_en_ligne/e_cours/module_17/item_311.pdf. Accessed June 4, 2010.

    • Search Google Scholar
    • Export Citation
  • 20.

    Schütte D, Pluschke G, 2009. Immunosuppression and treatment-associated inflammatory response in patients with Mycobacterium ulcerans infection (Buruli ulcer). Expert Opin Biol Ther 9: 187200.

    • Search Google Scholar
    • Export Citation
  • 21.

    Schütte D, Um-Boock A, Mensah-Quainoo E, Itin P, Schmid P, Pluschke G, 2007. Development of highly organized lymphoid structures in Buruli ulcer lesions after treatment with rifampicin and streptomycin. PLoS Negl Trop Dis 1: e2.

    • Search Google Scholar
    • Export Citation
  • 22.

    O'Brien DP, Robson ME, Callan PP, McDonald AH, 2009. “Paradoxical” immune-mediated reactions to Mycobacterium ulcerans during antibiotic treatment: a result of treatment success, not failure. Med J Aust 191: 564566.

    • Search Google Scholar
    • Export Citation
  • 23.

    Kestens L, Seddiki N, Bohjanen PR, 2009. Immunopathogenesis of immune reconstitution disease in HIV patients responding to antiretroviral therapy. Curr Opin HIV AIDS 3: 419424.

    • Search Google Scholar
    • Export Citation
  • 24.

    Lawn DS, Lockwood DN, 2007. Leprosy after starting antiretroviral treatment: an increasingly reported clinical problem but not a serious public health risk. BMJ 334: 217218.

    • Search Google Scholar
    • Export Citation
  • 25.

    Corti M, Villafañe MF, Ambroggi M, Sawicki M, Gancedo E, 2007. Soft tissue abscess and lymphadenitis due to Mycobacterium avium complex as an expression of immune reconstitution inflammatory syndrome after a second scheme of highly active antiretroviral therapy: case report. Rev Inst Med Trop Sao Paulo 49: 267270.

    • Search Google Scholar
    • Export Citation
  • 26.

    Singal A, Mehta S, Pandhi D, 2006. Immune reconstitution inflammatory syndrome in an HIV seropositive leprosy patient. Lepr Rev 77: 7680.

  • 27.

    Fock RA, Vinolo MA, Crisma AR, Nakajima K, Rogero MM, Borelli P, 2008. Protein-energy malnutrition modifies the production of interleukin-10 in response to lipopolysaccharide (LPS) in a murine model. J Nutr Sci Vitaminol (Tokyo) 54: 371377.

    • Search Google Scholar
    • Export Citation
  • 28.

    Rodriguez L, Gonzalez C, Flores L, Jimenez-Zamudio L, Graniel J, Ortiz R, 2005. Assessment by flow cytometry of cytokine production in malnourished children. Clin Diagn Lab Immunol 12: 502507.

    • Search Google Scholar
    • Export Citation
  • 29.

    Schaible UE, Kaufmann SH, 2007. Malnutrition and infection: complex mechanisms and global impacts. PLoS Med 4: e115.

  • 30.

    Funada H, Machi T, Matsuda T, 1991. Disseminated mycobacteriosis in patients with severe hematologic disorders. Kansenshogaku Zasshi 65: 12971303.

    • Search Google Scholar
    • Export Citation
  • 31.

    Skinsnes LK, Higa LH, 1976. The role of protein malnutrition in the pathogenesis of ulcerative “Lazarine” leprosy. Int J Lepr Other Mycobact Dis 44: 346358.

    • Search Google Scholar
    • Export Citation
  • 32.

    Stienstra Y, Van Der Werf TS, Oosterom E, Nolte IM, van der Graaf WT, Etuaful S, Raghunathan PL, Whitney EA, Ampadu EO, Asamoa K, Klutse EY, te Meerman GJ, Tappero JW, Ashford DA, van der Steege G, 2006. Susceptibility to Buruli ulcer is associated with the SLC11A1 (NRAMP1) D543N polymorphism. Genes Immun 7: 185189.

    • Search Google Scholar
    • Export Citation
  • 33.

    Mulder AA, Boerma RP, Barogui Y, Zinsou C, Johnson RC, Gbovi J, van der Werf TS, Stienstra Y, 2008. Healthcare seeking behaviour for Buruli ulcer in Benin: a model to capture therapy choice of patients and healthy community members. Trans R Soc Trop Med Hyg 102: 912920.

    • Search Google Scholar
    • Export Citation
  • 34.

    Kibadi K, Stragier P, Muyembe-Tamfum JJ, Pedrosa J, Portaels F, 2008. Follow-up of the first case of Mycobacterium ulcerans infection documented by PCR, genotyping and culture in the Republic of Congo-Brazzaville]. Méd Trop 68: 137143.

    • Search Google Scholar
    • Export Citation

Author Notes

*Address correspondence to Ghislain Emmanuel Sopoh, 01 BP 875 RP Cotonou, Bénin. E-mail:ghislainsop@yahoo.fr

Authors' addresses: Ghislain Emmanuel Sopoh, Ange Dodji Dossou, and Jean Gabin Houézo, Ministry of Health, Direction Nationale de la Protection Sanitaire (DNPS), Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) d'Allada, Allada, Atlantique, Bénin, E-mails: ghislainsop@yahoo.fr, anges_demon@yahoo.fr, and jghouezo@yahoo.fr. Luc Valère Brun, Université de Parakou, Faculté de Médecine, Unité d'Anatomie Pathologique, Parakou, Borgou, Bénin, E-mail: lbrun2004@yahoo.fr. Yves Thierry Barogui, Ministry of Health, Direction Nationale de la Protection Sanitaire (DNPS), Centre de Dépistage et de Traitement de l'Ulcère de Buruli de Lalo, Lalo, Couffo, Bénin, E-mail: yvesbaro@yahoo.fr. Dissou Affolabo and Séverin Y. Anagonou, Ministry of Health, Direction Nationale de la Protection Sanitaire (DNPS), Laboratoire de Référence des Mycobactéries (LRM), Cotonou, Littoral, Bénin, E-mails: affolabi_dissou@yahoo.fr and sanagonou@hotmail.fr. Roch Christian Johnson, Ministry of Health, Direction Nationale de la Protection Sanitaire (DNPS), Programme National de Lutte Contre la Lè et l'Ulcère de Buruli (PNLLUB), Cotonou, Littoral, Bénin, E-mail: rochjohnson@yahoo.fr. Luc Kestens, Institute of Tropical Medicine (ITM), Department of Microbiology, Immunology Unit, Antwerpen, Belgium, E-mail: lkestens@itg.be. Françoise Portaels, Institute of Tropical Medicine (ITM), Department of Microbiology, Mycobacteriology Unit, Antwerpen, Belgium, E-mail: fportaels@itg.be.

Save