Correspondence Clinical Letter
Clinical Letter Mycetoma caused by Nocardia brasiliensis in an immunocompetent patient
DOI: 10.1111/ddg.12331
Dear Editors, Mycetoma is a chronic primary skin infection that triggers destruction of skin and subcutaneous tissues [1]. Fungi (Eumycetoma) and bacteria (Actinomycetoma) are usual etiologic agents [2, 3], but about 60 % of mycetomas are caused by actinomycetes [3]. Nocardia represents a group of gram-positive aerobic bacteria found in soil, water and decomposing vegetation that usually manifests as an opportunistic infection in immunocompromised hosts [1, 4, 5]. The prevalence is influenced by climate and geography [5]. but Nocardi brasiliensis accounts for the majority of cutaneous infections [4–7]. Actinomycetoma usually results from traumatic injury related to contaminated soil [4]. In endemic areas, however, many people are exposed through minor skin injuries, but few develop the disease [3]; so, the immune response may play an important role in actinomycete infections. A 32-year-old male farmer, Fitzpatrick phototype IV, born and raised in a small town in southeastern Brazil, reported painless papular-nodular lesions on his back. First there were four lesions, which progressed insidiously to a single large plaque with multiple fistulas. He did not recall local trauma, did not smoke and did not have any comorbidities. Physical examination revealed a large tumefaction with multiple draining sites and fistulas with pus on his back (Figure 1a). Neither spontaneous drainage nor manually expressed material contained grains. Systemic examination showed a well-nourished man without fever, palpable regional lymphadenopathy or other systemic involvement. Laboratory screening showed only mild microcytic anemia. Chest radiography was normal. Serological tests for HIV, hepatitis
B and C were negative. We collected material from the nodules through fine needle aspiration and biopsy for staining and cultures for mycobacteria, common bacteria, acid-fast bacilli and fungi. N. brasiliensis was identified through typical bacterial and grain patterns in the histopathology, as well as white-yellow colonies on the fungal culture ( Figures 2, 3). No ELISA assays, PCR analysis or in vitro susceptibility testing were available. The patient was treated with trimethoprim-sulfamethoxazole (TMP-SMZ) (160–800 mg) twice daily for six months, with follow-up visits every three months. We observed complete remission after six months of treatment, sustained after 9 months and confirmed in quarterly evaluations after treatment (Figures 1b, c). Although grains were not found during expression of the fistula or in the purulent exudate, their absence is not unusual [6]. The morphology of the grains may help to identify causative agents of actinomycetoma, as stated by Welsh et al. [3, 8]. The N. brasiliensis grains, for instance, are typically white. Gram stain remains the first diagnostic tool [1]. Colonies have a folded, irregular surface, and their color varies according to the species [3]. Histological features help differentiate the granules based on the width of their filaments; purulent liquefying granulomas are frequent, as are infiltrates with polymorphonuclear microabscesses, macrophages, plasma cells and lymphocytes [8]. N. brasiliensis is phylogenetically related to Mycobacterium tuberculosis sharing morphological and antigenic characteristics [2]. Foamy cells might be implicated as reservoirs, providing a rich nutrient environment that favors bacterial intracellular survival [9]. Evidence suggests that N. brasiliensis induces an immunosuppressive local environment, probably related to IL-10 production [9]. Several factors may be involved in determining a good therapeutic outcome, but there is a lack of prospective controlled trials [4]. Management of nocardial infections must be individualized, considering in vitro antimicrobial susceptibility patterns, severity and site of infection, side effects, costs and treatment compliance [9]. Bonifaz et al. [8] recommended treating actinomycetomas due to N. brasiliensis with a combination of 4,4′-diaminodiphenylsulfone (dapsone, 100 to 200 mg per day) and
Figure 1 Patient’s back, before treatment (a). After three months of treatment (b). Six months after completion of treatment (c).
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210
903
Correspondence Clinical Letter
Figure 2 Histopathology × 40 exhibiting Nocardia brasiliensis in ZiehlNeelsen stain (a) and bacterial grain (b).
Figure 3 Histopathology × 40 exhibiting Nocardia brasiliensis grain with Gram stain (a) and in Grocott-Gomori methenamine silver (GMS) stain (b).
TMP-SMZ (80/400 to 160/800 mg per day). For pronounced forms or widespread infections, amikacin (15 mg per kg/day, in pulses of each 15–21 days, intravenously) can be additionally given, in 3 to 5 pulses. Subsequently, dapsone and/or TMP/SMZ can be given for a longer period [8]. Alternative antimicrobial agents include imipenem, meropenem, ceftriaxone, minocycline, moxifloxacin, levofloxacin, linezolid, and amoxicillin clavulanic acid [3–5]. Welsh et al. [3] stated that with amikacin-TMP-SMZ treatment a cure rate greater than 90 % is achieved, and in actinomycetoma, surgery as a method of treatment is exceptional. An average prevalence of mycetoma cases in Brazil was calculated as fewer than 0.01 : 100 000 habitants [10]. In this systematic review, N. brasiliensis was the causative agent in 5 % of the cases [10]. Although nocardiosis is rare in developed countries, N. brasiliensis can be recovered from soil in many of these lands, so it is important to be able to recognize this entity [10]. Conflict of interest None.
Correspondence to Juliana Martins Prazeres Sousa Rodovia Comandante João Ribeiro de Barros KM 225/226. CEP: 17039-800. E-mail: [email protected]
References 1
2
3
4 5
Juliana M. P. Sousa , Patrick A. Wachholz , Christiane S. Sette1, Gabriela F. Marques1, Jaison A. Barreto1 1
2
(1) Lauro de Souza Lima Institute, Bauru, São Paulo, Brazil (2) Botucatu Medical School, Universidade Estadual Paulista “Julio de Mesquita Filho” (FMB-UNESP), Botucatu, São Paulo, Brazil
904
6
Chedid MBF, Chedid MF, Porto NS et al. Nocardial infections: report of 22 cases. Rev Inst Med Trop São Paulo 2007; 49: 239–246. Castro-Matteotti B, Vera-Cabrera L, Ocampo-Candiani J et al. Immune response to Nocardia brasiliensis extracellular antigens in patients with mycetoma. Mycopathologia 2008; 165: 127–34. Welsh O, Vera-Cabrera L, Welsh E, Salinas MC. Actinomycetoma and advances in its treatment. Clin Dermatol 2012; 30: 372–81. Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc Mayo Clin 2012; 87: 403–7. Chen K-W, Lu C-W, Huang T-C et al. Cutaneous manifestations of Nocardia brasiliensis infection in Taiwan during 2002–2012 – clinical studies and molecular typing of pathogen by gyrB and 16S gene sequencing. Diagn Microbiol Infect Dis 2013; 77: 74–8. Fukuda H, Saotome A, Usami N et al. Lymphocutaneous type of nocardiosis caused by Nocardia brasiliensis: a case report and review of primary cutaneous nocardiosis caused by N. brasiliensis reported in Japan. J Dermatol 2008; 35: 346–53.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210
Correspondence Clinical Letter
7
8
López Martínez R, Méndez Tovar LJ, Lavalle P et al. Epidemiology of mycetoma in Mexico: study of 2 105 cases. Gac Médica México 1992; 128: 477–81. Bonifaz A, Vázquez-González D, Perusquía-Ortiz AM. Subcutaneous mycoses: chromoblastomycosis, sporotrichosis and mycetoma. J Dtsch Dermatol Ges 2010; 8: 619–627; quiz 628.
9
Salinas-Carmona MC, Rosas-Taraco AG, Welsh O. Systemic increased immune response to Nocardia brasiliensis co-exists with local immunosuppressive microenvironment. Antonie Van Leeuwenhoek 2012; 102: 473–480. 10 Van de Sande WWJ. Global burden of human mycetoma: A systematic review and meta-analysis. PLoS Negl Trop Dis 2013; 7: e2550.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210
905
Clinical Letter Mycetoma caused by Nocardia brasiliensis in an immunocompetent patient
DOI: 10.1111/ddg.12331
Dear Editors, Mycetoma is a chronic primary skin infection that triggers destruction of skin and subcutaneous tissues [1]. Fungi (Eumycetoma) and bacteria (Actinomycetoma) are usual etiologic agents [2, 3], but about 60 % of mycetomas are caused by actinomycetes [3]. Nocardia represents a group of gram-positive aerobic bacteria found in soil, water and decomposing vegetation that usually manifests as an opportunistic infection in immunocompromised hosts [1, 4, 5]. The prevalence is influenced by climate and geography [5]. but Nocardi brasiliensis accounts for the majority of cutaneous infections [4–7]. Actinomycetoma usually results from traumatic injury related to contaminated soil [4]. In endemic areas, however, many people are exposed through minor skin injuries, but few develop the disease [3]; so, the immune response may play an important role in actinomycete infections. A 32-year-old male farmer, Fitzpatrick phototype IV, born and raised in a small town in southeastern Brazil, reported painless papular-nodular lesions on his back. First there were four lesions, which progressed insidiously to a single large plaque with multiple fistulas. He did not recall local trauma, did not smoke and did not have any comorbidities. Physical examination revealed a large tumefaction with multiple draining sites and fistulas with pus on his back (Figure 1a). Neither spontaneous drainage nor manually expressed material contained grains. Systemic examination showed a well-nourished man without fever, palpable regional lymphadenopathy or other systemic involvement. Laboratory screening showed only mild microcytic anemia. Chest radiography was normal. Serological tests for HIV, hepatitis
B and C were negative. We collected material from the nodules through fine needle aspiration and biopsy for staining and cultures for mycobacteria, common bacteria, acid-fast bacilli and fungi. N. brasiliensis was identified through typical bacterial and grain patterns in the histopathology, as well as white-yellow colonies on the fungal culture ( Figures 2, 3). No ELISA assays, PCR analysis or in vitro susceptibility testing were available. The patient was treated with trimethoprim-sulfamethoxazole (TMP-SMZ) (160–800 mg) twice daily for six months, with follow-up visits every three months. We observed complete remission after six months of treatment, sustained after 9 months and confirmed in quarterly evaluations after treatment (Figures 1b, c). Although grains were not found during expression of the fistula or in the purulent exudate, their absence is not unusual [6]. The morphology of the grains may help to identify causative agents of actinomycetoma, as stated by Welsh et al. [3, 8]. The N. brasiliensis grains, for instance, are typically white. Gram stain remains the first diagnostic tool [1]. Colonies have a folded, irregular surface, and their color varies according to the species [3]. Histological features help differentiate the granules based on the width of their filaments; purulent liquefying granulomas are frequent, as are infiltrates with polymorphonuclear microabscesses, macrophages, plasma cells and lymphocytes [8]. N. brasiliensis is phylogenetically related to Mycobacterium tuberculosis sharing morphological and antigenic characteristics [2]. Foamy cells might be implicated as reservoirs, providing a rich nutrient environment that favors bacterial intracellular survival [9]. Evidence suggests that N. brasiliensis induces an immunosuppressive local environment, probably related to IL-10 production [9]. Several factors may be involved in determining a good therapeutic outcome, but there is a lack of prospective controlled trials [4]. Management of nocardial infections must be individualized, considering in vitro antimicrobial susceptibility patterns, severity and site of infection, side effects, costs and treatment compliance [9]. Bonifaz et al. [8] recommended treating actinomycetomas due to N. brasiliensis with a combination of 4,4′-diaminodiphenylsulfone (dapsone, 100 to 200 mg per day) and
Figure 1 Patient’s back, before treatment (a). After three months of treatment (b). Six months after completion of treatment (c).
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210
903
Correspondence Clinical Letter
Figure 2 Histopathology × 40 exhibiting Nocardia brasiliensis in ZiehlNeelsen stain (a) and bacterial grain (b).
Figure 3 Histopathology × 40 exhibiting Nocardia brasiliensis grain with Gram stain (a) and in Grocott-Gomori methenamine silver (GMS) stain (b).
TMP-SMZ (80/400 to 160/800 mg per day). For pronounced forms or widespread infections, amikacin (15 mg per kg/day, in pulses of each 15–21 days, intravenously) can be additionally given, in 3 to 5 pulses. Subsequently, dapsone and/or TMP/SMZ can be given for a longer period [8]. Alternative antimicrobial agents include imipenem, meropenem, ceftriaxone, minocycline, moxifloxacin, levofloxacin, linezolid, and amoxicillin clavulanic acid [3–5]. Welsh et al. [3] stated that with amikacin-TMP-SMZ treatment a cure rate greater than 90 % is achieved, and in actinomycetoma, surgery as a method of treatment is exceptional. An average prevalence of mycetoma cases in Brazil was calculated as fewer than 0.01 : 100 000 habitants [10]. In this systematic review, N. brasiliensis was the causative agent in 5 % of the cases [10]. Although nocardiosis is rare in developed countries, N. brasiliensis can be recovered from soil in many of these lands, so it is important to be able to recognize this entity [10]. Conflict of interest None.
Correspondence to Juliana Martins Prazeres Sousa Rodovia Comandante João Ribeiro de Barros KM 225/226. CEP: 17039-800. E-mail: [email protected]
References 1
2
3
4 5
Juliana M. P. Sousa , Patrick A. Wachholz , Christiane S. Sette1, Gabriela F. Marques1, Jaison A. Barreto1 1
2
(1) Lauro de Souza Lima Institute, Bauru, São Paulo, Brazil (2) Botucatu Medical School, Universidade Estadual Paulista “Julio de Mesquita Filho” (FMB-UNESP), Botucatu, São Paulo, Brazil
904
6
Chedid MBF, Chedid MF, Porto NS et al. Nocardial infections: report of 22 cases. Rev Inst Med Trop São Paulo 2007; 49: 239–246. Castro-Matteotti B, Vera-Cabrera L, Ocampo-Candiani J et al. Immune response to Nocardia brasiliensis extracellular antigens in patients with mycetoma. Mycopathologia 2008; 165: 127–34. Welsh O, Vera-Cabrera L, Welsh E, Salinas MC. Actinomycetoma and advances in its treatment. Clin Dermatol 2012; 30: 372–81. Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc Mayo Clin 2012; 87: 403–7. Chen K-W, Lu C-W, Huang T-C et al. Cutaneous manifestations of Nocardia brasiliensis infection in Taiwan during 2002–2012 – clinical studies and molecular typing of pathogen by gyrB and 16S gene sequencing. Diagn Microbiol Infect Dis 2013; 77: 74–8. Fukuda H, Saotome A, Usami N et al. Lymphocutaneous type of nocardiosis caused by Nocardia brasiliensis: a case report and review of primary cutaneous nocardiosis caused by N. brasiliensis reported in Japan. J Dermatol 2008; 35: 346–53.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210
Correspondence Clinical Letter
7
8
López Martínez R, Méndez Tovar LJ, Lavalle P et al. Epidemiology of mycetoma in Mexico: study of 2 105 cases. Gac Médica México 1992; 128: 477–81. Bonifaz A, Vázquez-González D, Perusquía-Ortiz AM. Subcutaneous mycoses: chromoblastomycosis, sporotrichosis and mycetoma. J Dtsch Dermatol Ges 2010; 8: 619–627; quiz 628.
9
Salinas-Carmona MC, Rosas-Taraco AG, Welsh O. Systemic increased immune response to Nocardia brasiliensis co-exists with local immunosuppressive microenvironment. Antonie Van Leeuwenhoek 2012; 102: 473–480. 10 Van de Sande WWJ. Global burden of human mycetoma: A systematic review and meta-analysis. PLoS Negl Trop Dis 2013; 7: e2550.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210
905
