Parise-Fortes et al. Journal of Venomous Animals and Toxins including Tropical Diseases 2014, 20:38 http://www.jvat.org/content/20/1/38 CASE REPORT Open Access Lepromatous leprosy and perianal tuberculosis: a case report and literature review Maria Rita Parise-Fortes1,3*, Joel Carlos Lastória1, Silvio Alencar Marques1, Maria Stella Ayres Putinatti1, Hamilton Ometto Stolf1, Mariângela Ester Alencar Marques2 and Vidal Haddad1 Abstract Leprosy is a chronic infectious disease caused by Mycobacterium leprae, a microorganism that usually affects skin and nerves. Although it is usually well-controlled by multidrug therapy (MDT), the disease may be aggravated by acute inflammatory reaction episodes that cause permanent tissue damage particularly to peripheral nerves. Tuberculosis is predominantly a disease of the lungs; however, it may spread to other organs and cause an extrapulmonary infection. Both mycobacterial infections are endemic in developing countries including Brazil, and cases of coinfection have been reported in the last decade. Nevertheless, simultaneous occurrence of perianal cutaneous tuberculosis and erythema nodosum leprosum is very rare, even in countries where both mycobacterial infections are endemic. Keywords: Mycobacteria, Leprosy, Tuberculosis, Erythema nodosum leprosum Background Mycobacterium leprae, the causative agent of leprosy that affects the skin and peripheral nerves, shows trop- ism for macrophages and Schwann cells. The disease presents a wide clinical spectrum that is closely related to the patient specific immune response. The benign type, referred as tuberculoid or paucibacillary, is charac- terized by a Th1 immune response and production of type 1 cytokines including IFN-γ, IL-2, IL-12, IL-15 and TNF-α, which are typical of strong cell-mediated im- munity. In lepromatous or multibacillary leprosy, the main characteristics comprise high levels of Th2-type cytokines such as IL-4, IL-5 and IL-10, high bacillary loads in skin lesions and reduced specific cellular im- munity [1,2]. Tuberculosis is caused byMycobacterium tuberculosis and is predominantly a disease of the lungs, with pulmonary tu- berculosis accounting for 70% of cases [3]. M. tuberculosis can disseminate to other organs, including lymph nodes, bones, meninges and other extrapulmonary locations [3]. * Correspondence: mfortes@fmb.unesp.br 1Department of Dermatology, Botucatu Medical School, São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu São Paulo State, Brasil 3Departamento de Dermatologia e Radioterapia, Faculdade de Medicina de Botucatu, UNESP, Distrito de Rubião Junior, Botucatu, SP CEP 18618-970, Brasil Full list of author information is available at the end of the article © 2014 Parise-Fortes et al.; licensee BioMed Ce Creative Commons Attribution License (http:/ distribution, and reproduction in any medium Domain Dedication waiver (http://creativecom article, unless otherwise stated. There are 9 million cases of active tuberculosis being re- ported annually and one third of the world’s population is supposed to be infected with Mycobacterium tuberculosis, although asymptomatically. Of these latent individuals, only 5-10% will develop active tuberculosis in their life- time [3-5]. Similarly, in the natural history of leprosy, less than 5% of the people exposed to M. leprae will develop clinical disease [6,7]. Infections with intracellular pathogens such as M. leprae and M. tuberculosis, in most cases, are controlled by the cell-mediated immune response, based on CD4+ Th1 cells [8]. Leprosy is a more prevalent cause of cutaneous infections than tuberculosis and, even in endemic countries, the coinfection is uncommon in both diseases. We report in this paper a case of perianal tuberculosis in a patient whose lepromatous leprosy status was diagnosed as a type 2 leprosy reaction. Case report A 59-year-old male patient was admitted to our university hospital (Botucatu, SP, Brazil) complaining of a perianal suppurative ulcer developed two months before the first medical consultation. He was under therapy with prednis- one 40 mg/day for six months due to a presumed diagno- sis of a drug reaction. On physical examination, a clean 10-cm diameter phagedenic perianal ulcer (Figure 1) and ntral Ltd. This is an Open Access article distributed under the terms of the /creativecommons.org/licenses/by/4.0), which permits unrestricted use, , provided the original work is properly credited. The Creative Commons Public mons.org/publicdomain/zero/1.0/) applies to the data made available in this mailto:mfortes@fmb.unesp.br http://creativecommons.org/licenses/by/4.0 http://creativecommons.org/publicdomain/zero/1.0/ Figure 1 Cutaneous tuberculosis: fagedenic perianal ulcer. Parise-Fortes et al. Journal of Venomous Animals and Toxins including Tropical Diseases 2014, 20:38 Page 2 of 6 http://www.jvat.org/content/20/1/38 two longitudinal suppurative ulcers on the inguino-crural region were observed. During investigation, and soon after reducing the corticosteroid dose, disseminated erythema- tous papules and nodules were observed in the upper limbs (Figure 2). Histopathology of the perianal ulcer revealed a dense his- tiocytic dermal infiltrate and a granulomatous inflammatory Figure 2 Lepromatous leprosy: erythematous papules and nodules on the upper limbs. response with central caseous necrosis (Figure 3). Fite- Faraco staining showed a few acid-fast bacilli and the hypothesis of cutaneous tuberculosis was raised. The histopathology of upper limbs papular and nodular le- sions showed foamy macrophages with globi of bacilli, suggesting lepromatous leprosy (Figure 4). The perianal and inguinal ulcers were considered uncommon mani- festations of type 2 leprosy developed when corticoster- oid was gradually diminished. The patient was treated as for multibacillary leprosy with multidrug therapy and thalidomide. Four weeks later, the patient had fever, weight loss, asthe- nia and worsening of the perianal ulcer (Figure 5), but without erythema nodosum leprosum. With this clinical picture, new investigation was developed. The tubercu- lin skin test was positive (20 × 20 mm) and culture of M. tuberculosis – using a biopsy sample from the peri- anal ulcer – on Löwenstein-Jensen medium was positive (Figure 6). Polymerase chain reaction (PCR) and DNA analysis from upper limb skin samples were positive for M. leprae (Figure 7). With the new information the pa- tient was finally diagnosed as presenting simultaneously lepromatous leprosy – type 2 reaction – and cutaneous tuberculosis expressed by the perianal ulcer. Screening for HIV, HBV or HCV infection as well as lung, renal or colon compromising were negative. Hence, the patient was treated with isoniazid, ethambutol and rifampin for nine months with complete healing of the perianal and in- guinal lesions after two months (Figure 8). After the tuber- culosis treatment, the patient was submitted to additional multidrug therapy for 12 months with dapsone, rifampin and clofazimine with complete cure of leprosy. Discussion Tuberculosis is one of the most important health concerns in the world, which causes relevant levels of morbidity Figure 3 Histopathological exam of the perianal ulcer showing a dense histiocytic infiltrate and central caseous necrosis. Figure 4 Skin nodule consisting of foamy macrophages with globi of bacilli. Fite-Faraco staining revealed the presence of lepromatous leprosy acid-fast bacilli. Parise-Fortes et al. Journal of Venomous Animals and Toxins including Tropical Diseases 2014, 20:38 Page 3 of 6 http://www.jvat.org/content/20/1/38 and mortality, particularly in many developing coun- tries, in spite of this being the era of human immuno- deficiency virus infection [9]. The number of tuberculosis cases in industrialized and developing countries has in- creased in recent years, followed by increasing multidrug resistance [10]. Multidrug resistance and HIV infection are predispos- ing factors for the disease, since the immune response of the patient plays a significant role on clinical manifest- ation of tuberculosis [10-12]. Extrapulmonary tubercu- losis accounts for 13% of all cases [4]. Nevertheless, cutaneous tuberculosis is uncommon and is reported to occur in less than 1.5% of the cases of extrapulmonary tuberculosis [13]. The present study reports a clinical case of perianal tuberculosis and lepromatous leprosy with type 2 reac- tion coinfection without any detected active pulmonary or gastrointestinal infection. The association between Figure 5 Cutaneous tuberculosis: phagedenic perianal ulcer showing worsening of the perianal ulcer after treatment for leprosy lesion, for two months. Figure 6 M. tuberculosis, positive culture on Löwenstein-Jensen medium at 37°C. Figure 7 M. leprae, positive polymerase chain reaction DNA analysis. Parise-Fortes et al. Journal of Venomous Animals and Toxins including Tropical Diseases 2014, 20:38 Page 4 of 6 http://www.jvat.org/content/20/1/38 lepromatous leprosy and perianal tuberculosis with ery- thema nodosum leprosum demonstrates an extremely uncommon occurrence. Perianal tuberculosis may manifest in the following forms: ulcer, fistula, abscess, lupoid infiltration or miliary. The most common type is the ulcerative lesion, which is likely to have well-defined boundaries and is characterized by mucopurulent discharge [14]. The lesion observed in Figure 8 Perianal ulcer completely healed with antituberculous treatment for two months. the present report was ulcerative with many bacilli, signal- ing an immunosuppressive status probably related to cor- ticosteroid therapy. Perianal tuberculosis has rarely been reported, even in countries where the disease is endemic, and the diagno- sis is impaired due to the lack of a pulmonary focus. The possibility of an association with intestinal tuberculosis should be further investigated [15,16]. Coinfection with pulmonary tuberculosis and leprosy type 1 reaction has been reported and the leprosy type 1 reaction was observed during the treatment of pulmon- ary tuberculosis [17]. According to Trindade et al. [17], a review of patients between 2004 and 2011 showed that only two patients with leprosy were diagnosed as coin- fected with pulmonary tuberculosis. The occurrence of both tuberculosis and leprosy in the same individual is not an unusual clinical condition, but it is scarcely re- ported in the literature, even in countries where both diseases are endemic [18]. Delobel et al. [19] reported a triple association of American cutaneous leishmaniasis, lepromatous leprosy and pul- monary tuberculosis. The authors suggested that the unre- sponsiveness of patient’s T cells to IL-12 in vitro, stimulated by either L. guyanensis, M. bovis BCG or M. leprae anti- gens, could be the evidence of patient’s T cells failure to produce an appropriate Th cell response. This was respon- sible for the triple reported coinfection. There are other reports in the literature of coinfection of leprosy and pul- monary tuberculosis as well as leprosy and disseminated tu- berculosis in HIV-infected patients [20-24]. Leprosy is a disease of poverty. Its diagnosis remains based on clinical signs and symptoms. Delayed diagnosis associated with nerve impairment and physical deform- ities is still common in several endemic areas throughout the globe. Improving the medical attention and infrastruc- ture and promoting sanitary education will provide earlier diagnosis and specific treatment, which are crucial to help interrupt the M. leprae transmission chain [25,26]. Both leprosy and tuberculosis pose significant health risks, making it important for physicians to diagnose accurately and provide appropriate treatment for patients [27]. CD4+ T cells, as well as the cytokines IL-12, IFN-γ and TNF-α, are critical in the control of M. tuberculosis and M. leprae infections, but the host factors that deter- mine why some individuals are protected from infection while others develop the disease are still unclear [28]. Hence, the reason why M. tuberculosis and M. leprae are able to evade host immune surveillance and persist in- side the macrophages remains to be understood. These pathogens inhibit phagosome-lysosome fusion and stop phagosome maturation at an early stage, thus allowing escape from microbicidal peptides [29]. Genetic factors of the host and of the pathogen itself may be associated with an increased risk for patients to Parise-Fortes et al. Journal of Venomous Animals and Toxins including Tropical Diseases 2014, 20:38 Page 5 of 6 http://www.jvat.org/content/20/1/38 develop active tuberculosis and leprosy [28]. The im- munologic deficits observed in leprosy are specific for M. leprae. Immunosupression has been observed to ren- der individuals susceptible to M. leprae and M. tubercu- losis in cases of transplantation, cancer chemotherapy and in treatment with antitumor necrosis factor agents [30-32]. However, the coinfection with lepromatous lep- rosy and tuberculosis probably depends on multiple fac- tors including low socioeconomic status, poor nutrition, chemotherapy-induced immunosuppression and defi- cient host immune response [27]. The present report shows a rare case which was prob- ably eased by the immunosuppressive effect of cortico- steroid therapy for six months. Cutaneous tuberculosis remains to be one of the most difficult conditions to diagnose in developing countries due to the lack of re- sources and the necessary observation of clinical and histopathologic findings [11,33,34]. To the best of our knowledge, this is the first case of lepromatous leprosy associated with erythema nodosum leprosum and peri- anal tuberculosis fully documented. Conclusion In the present study, we report an association of leproma- tous leprosy with type 2 reaction and perianal ulcerative tu- berculosis without previous or active pulmonary infection. Simultaneous occurrence of cutaneous tuberculosis and lepromatous leprosy is extremely infrequent, even in coun- tries where both mycobacterial infections are endemic. Ethics committee approval The case report was submitted for analysis and approved by the Research Ethics Committee of the Botucatu Medical School (CEP), in accordance with resolution 466/2012. Consent Written informed consent was obtained from the patient for publication of this case report and the figures. Competing interests The authors declare that they have no competing interests. Authors’ contributions All authors contributed to the design of the study and manuscript preparation. All authors have read and approved the final manuscript. Acknowledgments The authors would like to thank the photographer of the Department of Dermatology, Eliete Corrêa Soares, for the pictures of the patient. Author details 1Department of Dermatology, Botucatu Medical School, São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu São Paulo State, Brasil. 2Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP – Univ Estadual Paulista), Botucatu, São Paulo State, Brazil. 3Departamento de Dermatologia e Radioterapia, Faculdade de Medicina de Botucatu, UNESP, Distrito de Rubião Junior, Botucatu, SP CEP 18618-970, Brasil. 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Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Abstract Background Case report Discussion Conclusion Ethics committee approval Consent Competing interests Authors’ contributions Acknowledgments Author details References << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /PageByPage /Binding /Left /CalGrayProfile (Dot Gain 20%) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (U.S. Web Coated \050SWOP\051 v2) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Error /CompatibilityLevel 1.4 /CompressObjects /Tags /CompressPages true /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJobTicket false /DefaultRenderingIntent /Default /DetectBlends true /DetectCurves 0.1000 /ColorConversionStrategy /LeaveColorUnchanged /DoThumbnails true /EmbedAllFonts true /EmbedOpenType false /ParseICCProfilesInComments true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams true /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveDICMYKValues true /PreserveEPSInfo true /PreserveFlatness true /PreserveHalftoneInfo false /PreserveOPIComments false /PreserveOverprintSettings true /StartPage 1 /SubsetFonts true /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /CropColorImages true /ColorImageMinResolution 300 /ColorImageMinResolutionPolicy /OK /DownsampleColorImages true /ColorImageDownsampleType /Bicubic /ColorImageResolution 300 /ColorImageDepth -1 /ColorImageMinDownsampleDepth 1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages true /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /OK /DownsampleGrayImages true /GrayImageDownsampleType /Bicubic /GrayImageResolution 300 /GrayImageDepth -1 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1200 /MonoImageMinResolutionPolicy /OK /DownsampleMonoImages true /MonoImageDownsampleType /Bicubic /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False /CreateJDFFile false /Description << /ARA /BGR /CHS /CHT /CZE /DAN /DEU /ESP /ETI /FRA /GRE /HEB /HRV /HUN /ITA /JPN /KOR /LTH /LVI /NLD (Gebruik deze instellingen om Adobe PDF-documenten te maken voor kwaliteitsafdrukken op desktopprinters en proofers. 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