AMERICAN CUTANEOUS LEISHMANIASIS WITH UNUSUAL CLINICAL PRESENTATION AND RESPONSE TO TREATMENT

Andrea Claudia Bekner Silva FERNANDES Raíssa Bocchi PEDROSO Eneide Aparecida Sabaini VENAZZI Paulo Donizeti ZANZARINI Sandra Mara Alessi ARISTIDES Maria Valdrinez Campana LONARDONI Thaís Gomes Verzignassi SILVEIRA About the authors

Abstract

The clinical manifestations and prognosis of cutaneous leishmaniasis (CL) can be influenced by the immune response of the patient and the species of the parasite. A case of atypical clinical presentation of CL, with development of non-characteristic lesions, poor response to therapy, and a long time to resolution is reported. Confirmatory laboratory tests included parasite detection, indirect immunofluorescence, Montenegro skin test, polymerase chain reaction, and parasite identification by multilocus enzyme electrophoresis. The parasite was identified as Leishmaniabraziliensis. The lesion was unresponsive to three complete courses of N-methylglucamine antimoniate intramuscular, and to treatment with pentamidine. The patient did not tolerate amphotericin B. The lesion finally receded after treatment with intravenous N-methylglucamine antimoniate. It is essential to ensure the accuracy of diagnosis and the appropriate treatment, which can include the use a second choice drug or a different route of administration.

Leishmania braziliensis; Cutaneous leishmaniasis; Unusual clinical forms; Treatment


INTRODUCTION

American cutaneous leishmaniasis (ACL) is a major public health problem in the New World. Clinical presentation and outcome of ACL are associated with the host immune response and the infecting Leishmania specie11. Grimaldi G Jr, Tesh RB. Leishmaniases of the New World: current concepts and implications for future research. Clin Microbiol Rev. 1993;6:230-50.. In Brazil, cutaneous leishmaniasis (CL), mainly caused byLeishmania (Viannia) braziliensis, is one of the dermatological diseases that deserves more attention due to its magnitude, as well as the risk of deformities and psychological involvement22. Brasil. Ministério da Saúde. Manual de Vigilância da Leishmaniose Tegumentar Americana. 2ª ed. Brasília: Ministério da Saúde; 2013..

The most common clinical form is the classical ulcer, with an indurate raised outer border and sharply incised central crater that usually self-heals over a period of months. The usual clinical presentations of leishmaniasis are easily diagnosed by clinicians in endemic regions, but unusual forms may give rise to difficulties in the diagnosis and appropriate treatment22. Brasil. Ministério da Saúde. Manual de Vigilância da Leishmaniose Tegumentar Americana. 2ª ed. Brasília: Ministério da Saúde; 2013.. Cutaneous leishmaniasis can produce a large variety of atypical and rare forms. There has been an increase in the number of papers reporting unusual clinical presentations, both for the Old and the New World33. Adriano AL, Leal PA, Breckenfield, MP, Costa IS, Almeida C, Sousa AR. American tegumentary leishmaniasis: an uncommon clinical and histopathological presentation. An Bras Dermatol. 2013;88:260-2.,44. Calpovina M, Gomez EA, Uezato H, Kato H, Nonaka S, Hashiguchi. Atypical clinical variants in New World cutaneous leishmaniasis: disseminated, erysipeloid and recidiva cútis due to Leishmania (V.) panamensis. Am J Trop Med Hyg. 2005;73: 281-4.,55. Ceyhan AM, Yildirim M, Basak PY, Akkaya VB, Erturan I. A case of erysipeloid cutaneous leishmaniasis: atypical and unusual clinical variant. Am J Trop Med Hyg. 2008;78:406-8.,66. Crowe A, Slavin J, Stark D, Aboltins C. A case of imported Leishmania infantum cutaneous leishmaniasis; an unusual presentation occurring 19 years after travel. BMC Infect Dis. 2014;14:597.,77. Mings S, Beck JC, Davidson C, Ondo AL, Shanler SD, Berman J. Cutaneous leishmaniasis with boggy induration and simultaneous mucosal disease. Am J Trop Med Hyg. 2009;80:3-5.,88. Moravvej H, Barzegar M, Nasiri S, Abolhasani E, Mohebali M. Cutaneous leishmaniasis with unusual clinical and histological presentation: report of four cases. Acta Med Iran. 2013;51:274-8.,99. Sandoval-Juarez A, Minaya-Gómez G, Rojas-Palomino N, Falconi E, Cáceres O. Leishmaniosis cutanea: manifestación clínica inusual. Rev Peru Med Exp Salud Publica. 2014;31:595-7..

Meglumine antimoniate is considered the first choice drug for CL treatment in Brazil. The Ministry of Health recommends 10-20 mg/kg Sb5+ per day for a period of 20 days, by intravenous or intramuscular route. If no remission is observed, a new treatment cycle is administered for 30 days. In the absence of therapeutic response, the second choice drugs, amphotericin B or pentamidine, are used22. Brasil. Ministério da Saúde. Manual de Vigilância da Leishmaniose Tegumentar Americana. 2ª ed. Brasília: Ministério da Saúde; 2013.. Despite pentavalent antimonials (Sb5+) be considered first-line drugs used to treat CL caused by different species, an increase in treatment failure has been documented in several regions of the world1010. Goto H, Lindoso JA. Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther. 2010;8:419-33..

We report a case of a patient with an unusual clinical form of cutaneous leishmaniasis with poor response to antimonial therapy and development of non-characteristic lesions. The present study received approval from the Permanent Committee for Ethics in Research involving Humans (Process No. 533/2009) of the Universidade Estadual de Maringá. The patient agreed to participate in the study and signed a free informed consent form. Written consent was obtained from the patient and his wife for this publication.

CASE REPORT

A forty-five-year-old black male patient from Apucarana,Paraná, with one atypical lesion on the right side of his back was attended, in March 2009, in the LEPAC (Laboratório de Ensino e Pesquisa em Análises Clínicas) of the Universidade Estadual de Maringá, for cutaneous leishmaniasis (CL) laboratory diagnosis. The patient reported that the lesion had been present for approximately one month (Fig. 1A). The lesion was a rounded plaque, with a erythematous violaceous center, descamative ulcerated edges, surrounded by an extensive area of lichenification, measuring 20 cm. Based on clinical appearance, the differential diagnosis of the lesion included chronic simple lichen, psoriasis, squamous cell carcinoma, chromomycosis, cutaneous tuberculosis, syphilis, paracoccidioidomycosis, and sarcoidosis. Before seeking for medical attention, the patient used topical antibiotics, but the lesion persisted without improvement. The performed tests showed a positive Montenegro skin test (MST) with an induration of 10 mm and indirect immunofluorescence (IIF) positive for anti-Leishmania IgG antibodies, reaching a titer of 80.Leishmania amastigotes were detected in the material obtained by scraping of the lesion stained by Giemsa (Fig. 1B) and cultured in blood base agar (BBA). The BBA grown parasites were sent to the Coleção de Leishmania of Instituto Oswaldo Cruz (CLIOC), Rio de Janeiro, Brazil, for identification and the strains were confirmed as L. (V.) braziliensis (MHOM/BR/2009/3476). The species identification was performed by multilocus enzyme electrophoresis (MLEE). To exclude the possibility of coexisting infections, fungi and HIV investigations were performed with negative results.

Fig. 1
- (A) Initial lesion (one-month-old) on the right back of the patient. (B) Positive direct parasite search with characteristic amastigotes (arrow). (C) The lesion after meglumine antimoniate (120 ampoules), pentamidine, and amphotericin B treatments.

The patient was treated with 120 ampoules of intramuscular meglumine antimoniate (approximately 15 mg/kg Sb5+ per day) in three cycles of 20 days each at the Pronto Atendimento Municipal of Apucarana municipality. Approximately 40 days after the end of treatment (August 2009) the lesion was still active and new laboratory tests were performed. The IIF test was positive with a titer of 160 and the direct parasite search was negative.

About six months later (May 2010) the patient was submitted to another treatment with intravenous pentamidine (4 mg/kg per day) for seven days, which resulted in apparent healing of the lesion. In June 2010, the values of serum amylase (87 U/L) and creatinine (1.0 mg/dL) were normal. However, some months later, new papular lesions emerged, ulcerated and spread to the axillary region. In November 2010, the patient was admitted for treatment with amphotericin B desoxycholate (50 mg/day). The treatment was discontinued after three doses because the values of serum urea (88 mg/dL) and creatinine (3.1 mg/dL) were increased indicating renal failure. One additional course of pentamidine for 10 days was established (April 2011). There was a partial clinical resolution of lesions with the patient still presenting some residual lesions.

In February 2012, about three years after the onset of the lesion and despite the multiple treatments, the lesion was not healing. The lesion was an ulcerated plaque with erythematous fibrous bottom and verrucous edges, surrounded by a lichenification area in the right scapular region and posterior region of the right arm (Fig. 1C). New laboratory tests were performed. The direct parasite search revealed the presence of characteristic amastigotes of Leishmania spp., the IIF showed titer 320, and the polymerase chain reaction (PCR) for kDNA minicircles of the subgenusLeishmania (Viannia) was positive.

The patient was treated again with meglumine antimoniate by the intravenous route (3 ampoules per day) for approximately 40 days. Following this treatment, the lesion healed. Unfortunately, about a year after the end of the treatment, the patient died of a heart attack.

DISCUSSION

This report describes an unusual case of CL due to the clinical presentation. There was the development of non-characteristic lesions, poor response to therapy and a long time to resolution. The patient was referred to laboratorial diagnosis of CL because, although he lived in an urban area, he had worked in a rural area, near a dam in an endemic region of CL. According to the patient, the lesion had been present for approximately one month despite presenting 20 cm.

Laboratory diagnosis confirmed the clinical suspicion of CL, with positive results in the direct search of parasites, with few amastigotes in the examined slides, presence of IgG antibodies and positive MST. The antibody search tests are sensitive and specific, but they are associated to cross-reactivity with other diseases, mainly Chagas disease and visceral leishmaniasis22. Brasil. Ministério da Saúde. Manual de Vigilância da Leishmaniose Tegumentar Americana. 2ª ed. Brasília: Ministério da Saúde; 2013.,1111. Gontijo B, Carvalho MLR. Leishmaniose tegumentar americana. Rev Soc Bras Med Trop. 2003;36:76-80.. MST does not differentiate current and past disease (most often remains positive after treatment) and does not distinguish between infection and disease. MST presents an estimated 84% positivity in the cutaneous form of CL1111. Gontijo B, Carvalho MLR. Leishmaniose tegumentar americana. Rev Soc Bras Med Trop. 2003;36:76-80..

In the New World, about fifteen species of Leishmania were found in humans causing CL1212. World Health Organization. Control of the leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases. Geneva: WHO; 2010. (Tech. Rep. Ser. no. 949).. The three main species causing CL in Brazil are L. (V.) braziliensis, L. (V.) guyanensis andL. (L.) amazonensis22. Brasil. Ministério da Saúde. Manual de Vigilância da Leishmaniose Tegumentar Americana. 2ª ed. Brasília: Ministério da Saúde; 2013.. According to WHO, the CL clinical forms include localized, disseminated, diffuse, and atypical cutaneous and mucocutaneous leishmaniases1212. World Health Organization. Control of the leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases. Geneva: WHO; 2010. (Tech. Rep. Ser. no. 949).. Many factors can influence the clinical manifestations and prognosis of leishmaniasis, such as the immune response of the patient and the species of the parasite11. Grimaldi G Jr, Tesh RB. Leishmaniases of the New World: current concepts and implications for future research. Clin Microbiol Rev. 1993;6:230-50.,1313. Oliveira FS, Valete-Rosalino CM, Pacheco SJB, Costa FAC, Schubach AO, Pacheco RS. American tegumentary leishmaniasis caused by Leishmania (Viannia) braziliensis: assessment of parasite genetic variability at intra- and inter-patient levels. Parasit Vectors. 2013;6:189.. The parasite was identified as L. (V.) braziliensis, a prevalent species in southern Brazil and widely distributed in the country22. Brasil. Ministério da Saúde. Manual de Vigilância da Leishmaniose Tegumentar Americana. 2ª ed. Brasília: Ministério da Saúde; 2013.. This species can induce a wide spectrum of clinical and immunopathological manifestations1414. Silveira FT, Lainson R, Castro Gomes CM, Laurenti MD, Corbett, CEP. Immunopathogenic competences of Leishmania (V.) braziliensis and L. (L.) amazonensis in American cutaneous leishmaniasis. Parasite Immunol. 2009;31:423-31..

Atypical lesions of cutaneous leishmaniasis caused by different species of Leishmania has been reported. ADRIANO et al.33. Adriano AL, Leal PA, Breckenfield, MP, Costa IS, Almeida C, Sousa AR. American tegumentary leishmaniasis: an uncommon clinical and histopathological presentation. An Bras Dermatol. 2013;88:260-2. reported a case of an unusual presentation of American tegumentary leishmaniasis involving a solitary lesion on the ear lobe, without ulceration. CALPOVINA et al.44. Calpovina M, Gomez EA, Uezato H, Kato H, Nonaka S, Hashiguchi. Atypical clinical variants in New World cutaneous leishmaniasis: disseminated, erysipeloid and recidiva cútis due to Leishmania (V.) panamensis. Am J Trop Med Hyg. 2005;73: 281-4. described three distinct variants of CL (erysipeloid, recidiva cutis (LRC), and disseminated leishmaniasis (DL) in children, caused by L. (V.) panamensis. TURETZ et al.15 15. Turetz ML, Machado PR, Ko AI, Alves F, Bittencourt A, Almeida RP, et al. Disseminated leishmaniasis: a new and emerging form of leishmaniasis observed in northeastern Brazil. J Infect Dis. 2002;186:1829-34.described patients with disseminated leishmaniasis of acneiform, papular, nodular, and ulcerated types, caused by L. (V.) braziliensis. NEITZKE-ABREU et al.1616. Neitzke-Abreu HC, Venazzi MS, Scodro RBL, Zanzarini PD, Fernandes AC, Aristides SM, et al. Cutaneous leishmaniasis with atypical clinical manifestations: case report. IDCases. 2014;1:60-2. have also reported a case of CL with atypical clinical manifestations due to L. (V.) braziliensis. SANDOVAL-JUAREZ et al.9 9. Sandoval-Juarez A, Minaya-Gómez G, Rojas-Palomino N, Falconi E, Cáceres O. Leishmaniosis cutanea: manifestación clínica inusual. Rev Peru Med Exp Salud Publica. 2014;31:595-7.described an unusual clinical manifestation of CL caused by L. amazonensis, in a child that was treated with antimony, had partial remission of some lesions, and reactivation of the lesions following a chronic course.

In the case reported in the present study, the lesion was an atypical clinical form and was still active after three cycles of meglumine antimoniate administered intramuscularly. The peculiarity of this case of leishmaniasis with lesion in form of rounded plaque, descamative ulcerated edges, erythematous violaceous center, and presenting an extensive area of lichenification around the lesion, are uncommon clinical manifestations in CL.

In atypical cases of CL, it is important to rule out the possibility of co-infections. CL in AIDS patients in the New World shows multiple, polymorphic and relapsing lesions1212. World Health Organization. Control of the leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases. Geneva: WHO; 2010. (Tech. Rep. Ser. no. 949).. In this case, co-infection with HIV was discarded, thereby to fungal infection.

Despite the apparent healing after treatment with intravenous pentamidine, new papular lesions emerged, ulcerated and spread to the axillary region. The patient was treated with amphotericin B. The treatment was discontinued because the patient showed alterations in renal function tests. An additional course of pentamidine was administered, there was a partial clinical resolution of lesions, but some residual lesions remained. About nine months after, the lesion was an ulcerated plaque, reaching the right scapular region and posterior region of the right arm. Since there was no successful treatment with second-line drugs available, meglumine antimoniate was used again, but intravenously. Although there is no difference between the intramuscular and intravenous routes, as regards the efficacy and safety of the drug33. Adriano AL, Leal PA, Breckenfield, MP, Costa IS, Almeida C, Sousa AR. American tegumentary leishmaniasis: an uncommon clinical and histopathological presentation. An Bras Dermatol. 2013;88:260-2., the lesion finally receded after treatment with meglumine antimoniate administered intravenously.

Despite pentavalent antimonials (Sb5+) being considered first-line drugs used to treat CL caused by different species, an increase in treatment failure has been documented in several regions of the world44. Calpovina M, Gomez EA, Uezato H, Kato H, Nonaka S, Hashiguchi. Atypical clinical variants in New World cutaneous leishmaniasis: disseminated, erysipeloid and recidiva cútis due to Leishmania (V.) panamensis. Am J Trop Med Hyg. 2005;73: 281-4.. Studies conducted in Latin America have reported failure in CL treatment with this drug: 7% in Bolivia1717. Bermudez H, Rojas E, Garcia L, Desjeux P, Dujardin JC, Boelaert M, et al. Generic sodium stibogluconate is as safe and effective as branded meglumine antimoniate, for the treatment of tegumentary leishmaniasis in Secure Park, Bolivia. Ann Trop Med Parasitol. 2006;100:591-600., 16% in Brazil11. Grimaldi G Jr, Tesh RB. Leishmaniases of the New World: current concepts and implications for future research. Clin Microbiol Rev. 1993;6:230-50., and up to 39% in Colombia1818. Palacios R, Osorio LE, Grajalew LF, Ochoa MT. Treatment failure in children in a randomized clinical trial with 10 and 20 days of meglumine antimonate for cutaneous leishmaniasis due to Leishmania Viannia species. Am J Trop Med Hyg. 2001;64:187-93.. GUIMARÃES et al.1919. Guimarães LH, Machado PR, Lago EL, Morgan DJ, Schriefer A, Bacellara O, et al. Atypical manifestations of tegumentary leishmaniasis in a transmission area of Leishmania braziliensis in the state of Bahia, Brazil. Trans R Soc Trop Med Hyg. 2009;103:712-5. described two cases of atypical ACL that healed after three courses of antimony (15-20 mg/kg/day intravenously for 20 days) and 13 cases healed with amphotericin B, after failure of three or more courses of antimony. PIMENTEL et al.2020. Pimentel MI, Baptista C, Rubin ÉF, Vasconcellos ÉC, Lyra MR, Salgueiro MM, et al. American cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis resistant to meglumine antimoniate, but with good response to pentamidine: a case report. Rev Soc Bras Med Trop. 2011;44:254-6. reported a similar case of cutaneous leishmaniasis where the lesion relapsed following two systemic treatments with meglumine antimoniate. The patient was treated with amphotericin B, which was interrupted due to poor tolerance. Afterwards, the patient was submitted to intramuscular pentamidine, and no relapse was observed.

An atypical clinical form of CL with a difficult treatment response and a long time to resolution was the main contribution of this study. Reports of unusual and rare clinical forms of CL are relevant to physicians and researchers finding out whatLeishmania species are capable of, causing forms of difficult diagnosis and treatment. Moreover, the knowledge of these cases is essential to ensure the accuracy of diagnosis and the appropriate treatment of the patient, which can include the use a second-line drug or a different route of administration for the first-line drug.

REFERENCES

  • 1
    Grimaldi G Jr, Tesh RB. Leishmaniases of the New World: current concepts and implications for future research. Clin Microbiol Rev. 1993;6:230-50.
  • 2
    Brasil. Ministério da Saúde. Manual de Vigilância da Leishmaniose Tegumentar Americana. 2ª ed. Brasília: Ministério da Saúde; 2013.
  • 3
    Adriano AL, Leal PA, Breckenfield, MP, Costa IS, Almeida C, Sousa AR. American tegumentary leishmaniasis: an uncommon clinical and histopathological presentation. An Bras Dermatol. 2013;88:260-2.
  • 4
    Calpovina M, Gomez EA, Uezato H, Kato H, Nonaka S, Hashiguchi. Atypical clinical variants in New World cutaneous leishmaniasis: disseminated, erysipeloid and recidiva cútis due to Leishmania (V.) panamensis. Am J Trop Med Hyg. 2005;73: 281-4.
  • 5
    Ceyhan AM, Yildirim M, Basak PY, Akkaya VB, Erturan I. A case of erysipeloid cutaneous leishmaniasis: atypical and unusual clinical variant. Am J Trop Med Hyg. 2008;78:406-8.
  • 6
    Crowe A, Slavin J, Stark D, Aboltins C. A case of imported Leishmania infantum cutaneous leishmaniasis; an unusual presentation occurring 19 years after travel. BMC Infect Dis. 2014;14:597.
  • 7
    Mings S, Beck JC, Davidson C, Ondo AL, Shanler SD, Berman J. Cutaneous leishmaniasis with boggy induration and simultaneous mucosal disease. Am J Trop Med Hyg. 2009;80:3-5.
  • 8
    Moravvej H, Barzegar M, Nasiri S, Abolhasani E, Mohebali M. Cutaneous leishmaniasis with unusual clinical and histological presentation: report of four cases. Acta Med Iran. 2013;51:274-8.
  • 9
    Sandoval-Juarez A, Minaya-Gómez G, Rojas-Palomino N, Falconi E, Cáceres O. Leishmaniosis cutanea: manifestación clínica inusual. Rev Peru Med Exp Salud Publica. 2014;31:595-7.
  • 10
    Goto H, Lindoso JA. Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther. 2010;8:419-33.
  • 11
    Gontijo B, Carvalho MLR. Leishmaniose tegumentar americana. Rev Soc Bras Med Trop. 2003;36:76-80.
  • 12
    World Health Organization. Control of the leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases. Geneva: WHO; 2010. (Tech. Rep. Ser. no. 949).
  • 13
    Oliveira FS, Valete-Rosalino CM, Pacheco SJB, Costa FAC, Schubach AO, Pacheco RS. American tegumentary leishmaniasis caused by Leishmania (Viannia) braziliensis: assessment of parasite genetic variability at intra- and inter-patient levels. Parasit Vectors. 2013;6:189.
  • 14
    Silveira FT, Lainson R, Castro Gomes CM, Laurenti MD, Corbett, CEP. Immunopathogenic competences of Leishmania (V.) braziliensis and L. (L.) amazonensis in American cutaneous leishmaniasis. Parasite Immunol. 2009;31:423-31.
  • 15
    Turetz ML, Machado PR, Ko AI, Alves F, Bittencourt A, Almeida RP, et al. Disseminated leishmaniasis: a new and emerging form of leishmaniasis observed in northeastern Brazil. J Infect Dis. 2002;186:1829-34.
  • 16
    Neitzke-Abreu HC, Venazzi MS, Scodro RBL, Zanzarini PD, Fernandes AC, Aristides SM, et al. Cutaneous leishmaniasis with atypical clinical manifestations: case report. IDCases. 2014;1:60-2.
  • 17
    Bermudez H, Rojas E, Garcia L, Desjeux P, Dujardin JC, Boelaert M, et al. Generic sodium stibogluconate is as safe and effective as branded meglumine antimoniate, for the treatment of tegumentary leishmaniasis in Secure Park, Bolivia. Ann Trop Med Parasitol. 2006;100:591-600.
  • 18
    Palacios R, Osorio LE, Grajalew LF, Ochoa MT. Treatment failure in children in a randomized clinical trial with 10 and 20 days of meglumine antimonate for cutaneous leishmaniasis due to Leishmania Viannia species. Am J Trop Med Hyg. 2001;64:187-93.
  • 19
    Guimarães LH, Machado PR, Lago EL, Morgan DJ, Schriefer A, Bacellara O, et al. Atypical manifestations of tegumentary leishmaniasis in a transmission area of Leishmania braziliensis in the state of Bahia, Brazil. Trans R Soc Trop Med Hyg. 2009;103:712-5.
  • 20
    Pimentel MI, Baptista C, Rubin ÉF, Vasconcellos ÉC, Lyra MR, Salgueiro MM, et al. American cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis resistant to meglumine antimoniate, but with good response to pentamidine: a case report. Rev Soc Bras Med Trop. 2011;44:254-6.

Publication Dates

  • Publication in this collection
    2016

History

  • Received
    27 May 2015
  • Accepted
    08 July 2015
Instituto de Medicina Tropical de São Paulo Av. Dr. Enéas de Carvalho Aguiar, 470, 05403-000 - São Paulo - SP - Brazil, Tel. +55 11 3061-7005 - São Paulo - SP - Brazil
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