Revista6Vol89ingles_Layout 1 10/10/14 11:08 AM Página 925 REVIEW 925 s Update on cutaneous tuberculosis* Maria Fernanda Reis Gavazzoni Dias1 Fred Bernardes Filho1 Maria Victória Quaresma1 Leninha Valério do Nascimento2 José Augusto da Costa Nery3 David Rubem Azulay1,4 DOI: http://dx.doi.org/10.1590/abd1806-4841.20142998 Abstract: Tuberculosis continues to draw special attention from health care professionals and society in general. Cutaneous tuberculosis is an infection caused by M. tuberculosis complex, M. bovis and bacillus Calmette- Guérin. Depending on individual immunity, environmental factors and the type of inoculum, it may present var- ied clinical and evolutionary aspects. Patients with HIV and those using immunobiological drugs are more prone to infection, which is a great concern in centers where the disease is considered endemic. This paper aims to review the current situation of cutaneous tuberculosis in light of this new scenario, highlighting the emergence of new and more specific methods of diagnosis, and the molecular and cellular mechanisms that regulate the par- asite-host interaction. Keywords: Erythema Induratum; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis, Cutaneous INTRODUCTION Tuberculosis (TB) continues to draw special worsening of cutaneous tuberculosis and the emer- attention from health care professionals and society as gence of subclinical infections. The most common a whole. It still meets all the criteria for prioritization clinical presentations of infection by Mycobacterium of a public health disorder, i.e. large magnitude, vul- tuberculosis-associated IRIS are lymphadenitis or lym- nerability and transcendence.1 Cutaneous tuberculosis phadenopathy.7-9 is an infection caused by M. tuberculosis complex, M. Knowledge about TB infection and its clinical bovis and bacillus Calmette-Guérin (BCG), which management were outside the scope of most dermato- depending on individual immunity, environmental logical practices. However, the introduction of biolog- factors and type of inoculum may present varied clin- ic therapies demanded from dermatologists a deep ical and evolutionary aspects.2-4 and up-to-date knowledge of tuberculosis.10 Since 2009, the Brazilian Ministry of Health rec- This article provides relevant current informa- ommends the use of ethambutol as the fourth drug tion on the definition, epidemiology, recognition of associated with rifampicin, isoniazid and pyrazi- clinical presentation, microbiology and immunology namide to treat tuberculosis. It is recommended that of infectious agents, diagnostic methods and treat- cases of cutaneous TB should be discussed within the ment of cutaneous tuberculosis. health unit TB program.1,5 The association of TB with HIV infection repre- EPIDEMIOLOGY sents an additional challenge worldwide. An increase According to the World Health Organization in its incidence has been described in several countries (WHO), in 2011, there were about 8.8 million incident in recent years, especially in urban centers and regions cases of TB, 1.1 million deaths from TB among HIV- with high prevalence of human immunodeficiency seronegative persons and an additional 350,000 virus (HIV) infection.6 Complications related to deaths from HIV-associated TB. In the same year, immune reconstitution induced by antiretroviral ther- 84,137 cases of tuberculosis were reported in Brazil, of apy, known as immune reconstitution inflammatory which, 74,892 were newly diagnosed or retreatment syndrome (IRIS) may occur, including paradoxical cases and 2,755 were from other causes (unknown his- Received on 21.07.2013. Approved by the Advisory Board and accepted for publication on 26.09.2013. * Work performed at Professor Rubem David Azulay Dermatology Institute- Rio de Janeiro Santa Casa da Misericórdia Hospital (IDPRDA-SCMRJ) – Rio de Janeiro (RJ), Brazil. Financial Support: None. Conflict of Interest: None. 1 Instituto de Dermatologia Professor Rubem David Azulay - Santa Casa da Misericórdia do Rio de Janeiro (IDPRDA-SCMRJ) – Rio de Janeiro (RJ), Brazil. 2 Hospital Central do Exército (HCE) – Rio de Janeiro (RJ), Brazil. 3 Fundação Oswaldo Cruz (FIOCRUZ) - Rio de Janeiro (RJ), Brazil. 4 Pontifícia Universidade Católica do Rio de Janeiro (PUC-RJ) – Rio de Janeiro (RJ), Brazil. ©2014 by Anais Brasileiros de Dermatologia An Bras Dermatol. 2014;89(6):925-38. Revista6Vol89ingles_Layout 1 10/10/14 11:08 AM Página 926 926 Dias MFRG, Bernardes Filho F, Quaresma MV, Nascimento LV, Nery JAC, Azulay DR tory). Amongst the new cases, 56% had positive bacil- tions, cutaneous granulomas, fixed drug eruption and loscopy, 18% had negative smear, 12% were unknown, cutaneous tuberculosis.21 The World Health 14% were cases of extra pulmonary tuberculosis and Organization currently recommends that BCG vaccine 1% of unspecified TB. Regarding cases of retreatment, should be administered to all those living in areas of 35% were due to recurrence, 2% to therapy failure, endemic tuberculosis. In Brazil, the vaccine is part of 33% to abandonment of treatment and 29% to other the national immunization schedule and according to causes (unknown history).11 Records of TB in Brazil do the MH’s immunization manual it is indicated right not specify the cutaneous form, which led to lack of after birth, as early as possible.22 The interval between data on its incidence.1,5 vaccination and the development of skin lesions may About 20% of TB cases in children have extra- be of several months or years, with an average dura- pulmonary presentation. The most common forms tion of 1 year. Factors that may be responsible for the are: peripheral lymphadenopathy, pleural, bone and development of BCG reactions include inherent sus- meningoencephalic TB.12 ceptibility of the organism to BCG virulence, to the According to the Ministry of Health (MH), in amount of inoculum and the inoculation tech- 2011, the Brazilian states that reported most cases of nique.21,23,24 TB were Sao Paulo (16,630 cases), Rio de Janeiro (11,651), Bahia (5,257) and Rio Grande do Sul (5,031).13 IMMUNOLOGY IN TUBERCULOSIS Just as in leprosy and pulmonary tuberculosis, ETIOLOGICAL AGENT there is a concept of spectrum in cutaneous tuberculo- Mycobacterium tuberculosis bacillus, or bacillus sis. Based on bacteriological, histopathological and Koch (BK) is a transitional form between actino- immunological parameters, Sehgal et al proposed a mycetes and eubacteria. It belongs to class continuous spectrum extending from the greater cel- Schizomycetes, order Actinomycetales, family lular immunity pole, observed in lupus vulgaris, with Mycobacteriaceae and genus Mycobacterium. Robert active cellular immunity and apparently normal lev- Koch first described it on March 24th, 1882. This is a els of immunoglobulins, to scrofuloderma and cuta- non-spore-forming, nonmotile, non-toxin producer, neous miliary tuberculosis, which present a relatively strictly aerobic bacillus and a facultative intracellular less active cellular immunity and high humoral species. It has an extended growth period (16 to 20 response, as evidenced by elevated immunoglobulin hours) and doubling time (18 to 48 hours). These serum levels and low levels of C3.25,26 bacilli present acid-alcohol-resistant staining proper- The introduction of more specific and sensitive ties – i.e., they stain red by fuchsin and will not discol- diagnostic methods, as well as a greater understand- or by the actions of alcohol and acid, hence the name ing of the molecular and cellular mechanisms that reg- AFB – Acid-Fast Bacilli. Its genome has already been ulate the parasite-host interaction may contribute to sequenced.14-17 an efficient fight against tuberculosis. Although it may cause illness in men, M. bovis Immunosuppression, either due to a poor state of is considered a zoonotic disease that usually affects health, HIV infection or to the use of immunosuppres- tonsils, lymph nodes and intestine. It may rarely be sive drugs, represents the main trigger for active dis- the cause of the cutaneous form of TB. When causing ease development, caused by M. tuberculosis.27 lung disease, M. bovis is not easily transmitted and Tissue macrophages constitute one of the first therefore, there is a tendency for its disappearance.18,19 lines of defense against mycobacteria. After being Bacillus Calmette-Guerin (BCG) is a lyophilized phagocytized, the bacilli remain within the phago- vaccine developed in 1908, prepared from a live, some. After the phagosome-lysosome fusion, antigens attenuated strain of Mycobacterium bovis. Adverse can be processed and subsequently presented to T- events associated with BCG vaccine are uncommon, helper lymphocytes (CD4 +) through major histocom- but local or systemic complications may occur.20,21 patibility complex (MHC) class II. CD4 + type 1 cells They depend on the strain used and are more com- (Th1) play a major role in the immune response to mon amongst infants than adolescents. Ulceration, mycobacteria.27,28 subcutaneous abscess and suppurative lymphadenitis In the case of mycobacteria, it was demonstrat- occur in 0.4 per 1,000 vaccinations, appearing in the ed that apoptotic vesicles, originated from infected first 6 months after vaccination. Hypertrophic and cells and containing bacillary antigens associated to keloid scarring occur in 4 per million vaccinated. MHC class I, are able to specifically stimulate CD8 + T Systemic complications and fatal dissemination are cells also participating in the immune response to M. rare (<1.5 per million). Although generally safe, vac- tuberculosis.29