Cutaneous Tuberculosis: Epidemiological, Clinical, Diagnostic, and Therapeutic Update PDF

Anais Brasileiros de Dermatologia 2022;97(2):129---144 Anais Brasileiros de Dermatologia www.anaisdedermatologia.org.br...

Anais Brasileiros de Dermatologia 2022;97(2):129---144 Anais Brasileiros de Dermatologia www.anaisdedermatologia.org.br CONTINUING MEDICAL EDUCATION Cutaneous tuberculosis: epidemiological, clinical, diagnostic and therapeutic update! Arival Cardoso de Brito ∗ , Clivia Maria Moraes de Oliveira , Deborah Aben-Athar Unger , Maraya de Jesus Semblano Bittencourt A Exogenous cutaneous tuberculosis Tuberculous chancre and Tuberculosis verrucosa cutis Dermatology Service, Universidade Federal do Pará, Belém, PA, Brazil B. Endogenous cutaneous tuberculosis a) Bycontiguityorautoinoculation(Scrofuloderma,ori- ficial tuberculosis and some cases of lupus vulgaris) b) By hematogenic dissemination (Lupus vulgaris, Received 20 April 2021; accepted 26 July 2021 tuberculous gumma and acute miliary tuberculosis) Available online 4 January 2022 C. Tuberculids - Papulonecrotic tuberculid - Lichen scrofulosorum D. Cutaneous tuberculosis secondary to BCG vaccination Abstract Tuberculosis is certainly one of the diseases considered to be ancient on planet KEYWORDS Earth. The etiological agent of tuberculosis is Mycobacterium tuberculosis. This terrible bac- Epidemiology; terial infection still results in severe socioeconomic consequences to date, and its complete Mycobacterium eradication represents a great challenge. It constitutes one of the most important public health tuberculosis; problems in developing countries. According to the World Health Organization, this infection Pathogenesis, results in more than 4,000 deaths daily worldwide, with 10.4 million being affected annually homeopathic; and 1.5 million deaths from TB every year. With the emergence of the HIV/AIDS pandemic, Tuberculosis; the disease became the main cause of morbidity and mortality in patients infected with the Tuberculosis, human immunodeficiency virus. Cutaneous tuberculosis is a rare infection that represents 1% to cutaneous 1.5% of extrapulmonary tuberculosis, whose etiological agents are Mycobacterium tuberculosis, Mycobacterium bovis, and the attenuated form of the bacillus Calmette-Guérin (BCG vaccine). Cutaneous tuberculosis can be exogenous; endogenous: caused by contiguity or autoinocula- tion and by hematogenous spread; induced by the Calmette-Guérin bacillus and manifest as a tuberculid. The diagnosis of the infection is carried out through the direct test, culture, histopathology, tuberculin skin test, polymerase chain reaction, interferon-gamma release assay, and genotyping. Drugs used comprise isoniazid, rifampicin, pyrazinamide and ethambutol. © 2021 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Introduction Tuberculosis (TB) is an ancient, cosmopolitan infectious dis- ease caused by Mycobacterium tuberculosis that occurs with greater incidence in developing countries, constituting one ! Study conducted at the Dermatology Service, Universidade Fe- of the most serious public health problems, a constant threat deral do Pará, Belém, PA, Brazil. to health, which incapacitates and causes the death of a ∗ Corresponding author. large number of people. TB is considered by the World E-mail: [email protected] (A.C. Brito). Health Organization (WHO) as a worldwide disease with https://doi.org/10.1016/j.abd.2021.07.004 0365-0596/© 2021 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).  A.C. Brito, C.M. Oliveira, D.A. Unger et al. more than 4,000 deaths daily, 10.4 million infected indi- Etiology and pathogenesis viduals annually, and 1.5 million deaths from this infection every year. With the emergence of the HIV/AIDS pandemic, Mycobacterium tuberculosis was identified and isolated by the disease is the leading cause of morbidity and mortal- Robert Koch in 1882. It is an obligate intracellular, aero- ity in patients infected with the Human Immunodeficiency bic, straight or slightly curved, immobile, non-sporulating Virus (HIV).1---3 In 2018, 484,000 cases of rifampicin-resistant pathogen, measuring 1 to 10 !m long and 0.2 to 0.6 !m wide, tuberculosis were registered worldwide, of which 78% were an acid-fast bacillus (AFB), with the ability to survive and multidrug-resistant TB (MDR-TB).1---8 multiply inside macrophages. Its genome consists of approx- China, India and Indonesia account for 45% of TB cases imately 4,000 genes, of which about 200 are responsible for worldwide.1,2,9 Regarding the Southeast Asia and regions of encoding enzymes for fatty-acid metabolism, and another Africa, its mortality rate represents 85% of all deaths due to 170 encode families of proteins related to antigenicity, some tuberculosis.1,2,9---11 related to the metabolism of the bacillus and constituents In 2018, the disease caused 4,490 deaths in Brazil. In of the cell wall --- lipids, proteins, carbohydrates --- however, 2019, 73,864 new cases of TB were registered in Brazil --- most genes play an important role in the invasion of the an incidence of 35.0 cases/100,000 inhabitants. In Brazil, immune system.10,11,13,17,18 The high concentration of lipids an enormous increase in new cases of TB-HIV coinfection on the cell wall is responsible for the resistance/survival of was detected between 2010 and 2018.3---5 The risk of acquir- the microorganism; nevertheless, it shows sensitivity to heat ing TB depends on the coexistence of conditioning factors and ultraviolet radiation.9---11,18 such as genetic factors, age, sex, malnutrition, alcoholism, Tuberculosis research has played an important role in the smoking status, environmental factors, the immune system birth of immunology field of studies; however, the relation- status of each individual --- the increased use of immunosup- ship between the two has been ambivalent from the start.19 pressive drugs for the treatment of autoimmune diseases, Chen et al. propose that: ‘‘proteins are the most impor- neoplasms, transplant recipients --- development of MDR-TB, tant antigens of M. tuberculosis and can induce T-cell HIV infection, previous pulmonary disease, in addition to immune responses and other allergic reactions, includ- other comorbidities.1---10 ing late-onset hyperreactive cell immune responses. The Studies have reported that the immunosuppressive condi- caseous necrosis that occurs in the disease is induced by tion, determined by HIV/AIDS infection, predisposes to the lipoids.’’9 contagion and illness of afected individuals. The chance that The T-cell immune response act in the host defense infection with the bacillus will develop into tuberculosis in mechanism against bacteria, dendritic cells, activated immunocompetent individuals is 10% over one’s lifetime, macrophages, which phagocytose and destroy the mycobac- whereas it may reach 10% each year in those infected with terium, for antigen presentation to lymphocytes, in which a HIV.12 series of biological events are processed, highlighting the Extrapulmonary TB represents 20% of the cases of the important protective function of CD4+ and CD8+ T lym- disease, which includes pleural TB, osteoarticular TB, phocytes, which secrete cytokines to eliminate the bacillus genitourinary TB, ocular TB, abdominal TB, breast TB, tuber- of Koch (BK).9,13,15 According to Sehgal et al.19 one can culous meningitis, and pericarditis, cutaneous tuberculosis, consider the spectral concept in cutaneous tuberculosis, among other affected organs.9,11,13,14 based on bacteriological, histopathological and immunolog- Cutaneous tuberculosis (CTB) is a rare form of mycobac- ical parameters, similarly to what is described in leprosy teriosis that accounts for 1% to 2% of all forms of and pulmonary tuberculosis. At one end, lupus vulgaris, with extrapulmonary tuberculosis.9 The main etiological agent active cell immunity and apparently normal immunoglobu- is Mycobacterium tuberculosis and occasionally Mycobac- lin, and at the other end, scrofuloderma, with less active cell terium bovis and the bacillus Calmette-Guérin (BCG vaccine, immunity and increased humoral response, evidenced by an attenuated strain of M. bovis).3,8---11,15 elevated serum levels of immunoglobulins and reduced C3.20 In 1826, Théophile Laënnec (1781---1826), the inventor of T-cells are responsible for the polarization of the dis- the stethoscope (1819), described the first case of CTB in the ease in the host since they can restrain M. tuberculosis, world that killed Laënnec himself. Robert Koch (1843---1910) developing the paucibacillary form or, through immunologi- identified and isolated M. tuberculosis only in 1882.7---9,13 cal suppression, allow the survival of the pathogen, leading It is important to emphasize that there are infections to the multibacillary form. The Th1 and Th17 pathways that are not caused by the Mycobacterium tuberculosis are the main effectors involved in the pathogenesis of TB, complex and by Mycobacterium leprae and Mycobac- mediating protection against the etiological agent. The reg- terium lepromatosis, but produced by non-tuberculous or ulatory T (Treg) cells subgroup also plays an important role atypical mycobacteria (NTM), among which the following in the process, as it maintains the cell-mediated immunity stand out: Mycobacterium avium complex (MAC), Mycobac- effector cells in homeostasis.20---22 The most important com- terium ulcerans, Mycobacterium marinum, Mycobacterium ponent of the defense against TB through the Th1 pathway haemophilum, Mycobacterium fortuitum, Mycobacterium is the production of the cytokine IFN-", which activates chelonae, Mycobacterium kansasii, Mycobacterium absces- macrophages and stimulates phagocytosis, phagosome mat- sus, Mycobacterium scrofulaceum, Mycobacterium simiae, uration, production of reactive nitrogen intermediates and Mycobacterium malmoense, Mycobacterium xenopi.7---11,13 antigen presentation. Although IFN-" is one of the most CTB is prevalent in young adults, particularly women, important cytokines for the protective response against M. tuberculosis verrucosa cutis predominates in males, and ery- tuberculosis, it is not enough to control the pathogen.23---25 thema induratum of Bazin in females.8---11,16 The Th17 cells produce IL-17, which plays a major protec- 130 IL-17 is mostly associated with induction of proinflammatory programs TH1 IFNg MACROFAGI FAGOCITOSI associated with chemokine secretion and neutrophil recruitment, early recruitment of neutrophils to Mtb lungs is associated with early granuloma formation.In addition, neutrophils and macrophages cooperate for efficient mycobacterial killin  Anais Brasileiros de Dermatologia 2022;97(2):129---144 tive role in TB, observed through the survival of neutrophils d) Tuberculids: papulonecrotic tuberculid; lichenoid tuber- in the early stages of infections, providing control of the culid (lichen scrofulosorum) bacterial load.26---30 e) Facultative tuberculids: erythema induratum of Bazin - The suppressive mediation of Treg cells occurs mainly nodular vasculitis. through the secretion of the immunosuppressive cytokine TGF-#, which has an anti-inflammatory effect.31---33 In patients with cutaneous tuberculosis, Treg cells produce a Tuberculous chancre significant amount of TGF-#, which plays an important role in CD4+, CD25+ Treg expansion and also inhibits Th17 cell Tuberculous chancre (TC) or primary inoculation tuberculo- polarization.22 sis results from the direct penetration of M. tuberculosis The main target of M. tuberculosis in the human species into the skin and/or mucous membranes through trauma, is the lungs; however, all organs and systems of the host wounds, preexisting dermatosis, surgical procedures with can be infected by the microorganism. Most of the infec- contaminated material in people who do not have innate tions occur through the airways and 80% of TB clinical forms or adaptive immunity to M tuberculosis. Individuals also are pulmonary.7---11,15,17 Skin integrity is very effective in acquire the disease through mouth-to-mouth breathing, preventing BK entry, but solutions of continuity of the muco- circumcision, injections with contaminated hypodermic cutaneous integument will favor infection of the host by the needles, after tattooing procedures, piercings, at insulin BK and, therefore, cutaneous and/or mucosal tuberculous application sites. Infection of the oral mucosa by M. bovis manifestations. 7,8,11,17 can occur by ingestion of unpasteurized milk and by dental extraction. It is the most common form in children; how- ever, adolescents and young adults can also be infected in Clinical manifestations and classification this way.7---11,13,34 The clinical manifestations of CTB polymorphism can be explained by factors such as the pathogenicity of the bacte- Clinical manifestations rial strain, the host immune status, previous treatment, or LESIONE ULCERATA+LINFONODALE local factors, including proximity to lymph nodes.8---11,17 TC manifests two to four weeks after infection as a papule, The polymorphous lesions of CTB include papules, nod- infiltrated plaque or nodule that develops into an ulcera- ules, infiltrated plaques, ulcers, gummas, verrucous lesions. tive lesion located more frequently on the face (including Their differential diagnosis is mandatory with other diseases the conjunctiva), upper limbs (mostly the hands) and lower of similar clinical expression. This lesion polymorphism has limbs. The ulcer is painless, shallow, with a granular back- led to the proposition of several complex and controversial ground, an infiltrated base that can reach a few centimeters classifications. in diameter, and is difficult to heal. After two to eight The bacterial load is the basis for a proposed classifica- weeks, lymphangitis and regional lymph node disease ensue, tion for the disease, which is analogous to the Ridley and constituting the primary tuberculous complex in the skin, Jopling classification for leprosy and includes: similar to the Ghon complex of the lung.7 The lymph nodes may liquefy, ulcerate and eliminate necrotic/necropurulent a) The multibacillary form --- low immunity to BK, including material. Paronychia resulting from infection of the fingers tuberculous chancre, tuberculosis orificialis, scrofulo- by the bacillus is not so rare.7 derma, acute miliary tuberculosis, and tuberculous gumma. Histopathology b) The paucibacillary form --- high immunity to M. tubercu- losis, including verrucous tuberculosis, lupus vulgaris and An acute inflammatory infiltrate of neutrophils can be seen tuberculids. at the beginning of the infectious process, followed a few weeks later by granuloma organization, associated with The classification for TB based on more robust criteria caseous necrosis and the presence of numerous acid fast --- pathogenesis, anatomopathological analysis, immune sys- bacilli (AFB), demonstrated by Fite-Faraco or Ziehl-Neelsen tem, clinical picture --- accepted worldwide by those who stains. study mycobacteriosis will be adopted in this work:7---9,11,16,17 a) Exogenous cutaneous tuberculosis: tuberculous chancre Diagnosis and tuberculosis verrucosa cutis. b) Endogenous cutaneous tuberculosis: Laboratory confirmation of the etiological agent by direct screening and culture for AFB, PPD (purified protein deriva- tive), histopathological analysis, interferon-gamma release Contiguity or self-inoculation (scrofuloderma, tuberculo- assay (IGRA) and polymerase chain reaction (PCR) for BK. sis orificialis and some cases of lupus vulgaris); Hematogenous spread (lupus vulgaris, gummatous tuber- culosis and acute miliary tuberculosis). Differential diagnosis c) Cutaneous tuberculosis caused by bacillus of Calmette- It must be established with NTM, syphilis, bartonellosis, Guerin (BCG vaccine); post-vaccination lupus vulgaris. sporotrichosis, and leishmaniasis. 131 LA BASE DELL’ULCERA, CHE E’ INDOLORE, SI INFILTRA SEMPRE PIU’ E QUINDI L’ULCERA DIVENTA DURA. LA LINFOADENOPATIA PUO’ ANDARE INCONTRO A FISTOLIZZAZIONE  A.C. Brito, C.M. Oliveira, D.A. Unger et al. PLACCA IPERKERATOSICA ESTENS.CENTRIFUGA FOCI DI SECREZ.PURULENTA Figure 1 (A), Tuberculosis verrucosa cutis (TVC): verrucous plaque with centrifugal expansion on the left arm. (B), TVC: epidermis with focal hyperplasia and dermis showing granulomatous inflammation involving follicular structures and vessels, (Hematoxylin & eosin, ×40). Tuberculosis verrucosa cutis cosis, Tuberculosis (other forms), NTM, verrucous lesions, carcinoma, keratoacanthoma, bromoderma, iododerma, Tuberculosis verrucosa cutis results from the exogenous hypertrophic lichen planus. inoculation in individuals previously infected with BK, with high immunity to the microorganism. It is the most common paucibacillary variant in healthcare professionals --- physi- Scrofuloderma cians, pathologists, veterinarians, biomedical technicians, nurses, autopsy technicians --- in farmers, butchers and is Scrofuloderma or tuberculosis cutis colliquative is the most unusual in people with other activities (Fig. 1A).7---11 frequent form of TB in developing countries, being prevalent in children and young adults, but it also affects the elderly. Clinical manifestations Depending on the host’s immune system and other condition- ing factors, it can affect the host in both the multibacillary Initially, the lesion is a papule/papulo-pustule with an ery- and paucibacillary clinical forms. thematous halo or a nodule with hyperkeratosis on the surface, developing into a verrucous plaque with centrifugal growth, sharp edges, and the presence of purulent secretion Clinical manifestations foci. The lesion is usually single, preferably located on the hands, but other areas of the skin may be involved, such as M. tuberculosis infection develops in lymph nodes, bones, the lower limbs, particularly in children.7,8,13,16,17 This lesion joints, as tuberculous epididymitis, or orchiepididymitis, eventually progresses to spontaneous healing with atrophic and the overlying skin is affected through contiguity by the scarring. mycobacteria. The coexistence of pulmonary TB is seen in most cases of scrofuloderma.7---9,11,16,17 The initial lesion is a subcutaneous nodule --- single or Histopathology multiple --- initially firm, which progressively increases in size. After several weeks, it softens, ruptures, resulting in Hyperkeratotic pseudoepitheliomatous hyperplasia is fistulas and ulceration, with the elimination of necrotic or observed and, a lymphocytic inflammatory infiltrate, necro-purulent material. They are known as cold abscesses. neutrophil abscesses in association with epithelioid cell The cervical, axillary, supraclavicular, and inguinal lymph granulomas, Langhans-type multinucleated cells, and node chains are most frequently involved in this form of caseous necrosis are seen in the dermis. AFB are scarce or tuberculosis (Figs. 2A and 2B) difficult to identify (Fig. 1B). Diagnosis Histopathology Clinical suspicion is confirmed through bacilloscopy, culture, The epidermis is atrophic or ulcerated, depending on the IGRA, PPD, PCR, or histopathology. biopsied lesion. The dermis and subcutaneous tissue show caseous necrosis, surrounded by macrophage granulomas, Differential diagnosis Langhans-type multinucleated giant cells and a small num- ber of lymphocytes. AFB are scarce. In most cases, M. It includes the verrucous syndrome (PLECT) --- (Paracoc- tuberculosis is difficult to demonstrate by special stains cidioidomycosis, Leishmaniasis, Sporotrichosis, Chromomy- (Fig. 2C). 132 scrofuloderma (tubercolosi cutanea colliquativa) è il prototipo dell’affezione cutanea per contiguità, derivante da una tubercolosi linfonodale, osteoarticolare o più raramente epididimale  Anais Brasileiros de Dermatologia 2022;97(2):129---144 Figure 2 (A), Scrofuloderma --- nodules/gummas and ulcerations on the cervical and right mastoid regions associated with lymph node tuberculosis. (B), Scrofuloderma --- infiltrated and ulcerated lesions on the right clavicular region. (C), Scrofuloderma --- caseation necrosis surrounded by granulomatous inflammation with a palisade of macrophages and Langhans-type multinucleated giant cells, (Hematoxylin & eosin, ×40). Figure 3 (A), Tuberculosis orificialis (tuberculosis cutis orificialis) --- Ulcerovegetating lesion affecting the labia majora and minora. (B), TB orificialis --- ulcerated epidermis and massive dermal granulomatous inflammatory infiltrate, (Hematoxylin & eosin, ×40). (C), TB orificialis --- granuloma associated with caseation necrosis, (Hematoxylin & eosin, ×200). Pictures by: Dr. Maraya Bittencourt. 133  A.C. Brito, C.M. Oliveira, D.A. Unger et al. Diagnosis Diagnosis Clinical findings are complemented by laboratory tests: PPD Clinical aspect of the lesions, complementary exams, inves- (strong reactor), culture in specific media, histopathology, tigation of TB in other organs, especially in the lungs. IGRA, PCR for BK. Differential diagnosis Differential diagnosis Consider recurrent aphthous stomatitis, syphilis, and other The following should be considered: paracoccidioidomyco- sexually transmitted infections with a clinical ulcerative sis, actinomycosis, sporotrichosis, syphilitic gumma, NTM, characteristic, deep mycoses, and malignant neoplasms, hidradenitis suppurativa. especially squamous cell carcinoma.35 Tuberculosis orificalis Lupus vulgaris Tuberculosis orificalis (TO), also known as acute tuberculous Lupus vulgaris (LV) is a type of endogenous, chronic cuta- ulcer and ulcerative cutaneous and mucosal tuberculo- neous tuberculosis, caused by contiguity or self-inoculation sis, results from self-inoculation of M. tuberculosis in the (some cases) and by hematogenous or lymphatic spread, in mucosa and periorificial skin in individuals with low immu- individuals with high or moderate immunity to M. tuber- nity and tuberculosis in internal organs --- lungs, urogenital, culosis, who are tuberculin-positive, with paucibacillary gastrointestinal, in addition to other activity foci. This rare disease, which has a higher prevalence in females than in form of TB has a higher incidence in the elderly, who males, affecting any age group. The infection occurs from a usually have an immunological deficiency and non-reactive tuberculosis focus of pulmonary, osteoarticular, lymph node PPD.7---9,11,16---18,35,36 origin, or from other organs. It can exceptionally develop Considering the multiple differential diagnoses that gen- after BCG vaccination.11---13,16,18,36 ital ulcers raise with other diseases that manifest with APPLE JELLY ATROPHIC CENTER this type of lesion - viral, bacterial, fungal infections, Clinical manifestations ULCERATION pre-cancerous, neoplastic lesions, and other causes - it is essential to carefully investigate for an accurate diagnosis.37 LV is manifested by the presence of an erythematous- Genital tuberculosis occurs more frequently in old, post- brownish papule or nodule with a smooth or keratotic menopausal women, almost always related to an active surface, a gelatinous consistency that, on diascopy, looks or reactivated tuberculous focus, with a predominance of like ‘‘apple jelly’’. lesions in the fallopian tubes, in the endometrium, and The lesion is usually single; however, it can be multiple. rarely in the vulvovaginal region. However, the develop- Its preferred location is on the face --- nose, malar regions, ment of a painful ulcer of tuberculous etiology on the left chin, ears --- but other regions can be affected, such as labia majora in a 14-year-old virgin female is an exceptional the cervical area, upper and lower limbs. The initial lesion report in the literature.37 The record is a warning to include progresses to a plaque with centrifugal expansion, with an TO among the proposed diagnoses, even when it appears in atrophic center that can ulcerate (Figs. 4A and 4B). adolescents who have not yet started sexual activity. Published case reports with different types of LV lesions have resulted in variants, as follows: psoriasiform, eczema- Clinical manifestations tous, annular, ulcerative, vegetating, hypertrophic, and scarring plaques.9,38 the ulcerative and vegetating muti- The sites most often affected by mycobacterioses are lating variants cause severe deformities in the affected the oral cavity, external genitalia, Fallopian tubes, sites.7---9,13,17 endometrium, anal/perianal regions (Fig. 3A). The mucosa can be compromised by direct inoculation Oral cavity lesions can extend contiguously to the phar- of m. tuberculosis or from the expansion of a skin lesion. ynx and larynx in the form of very painful ulcerations. The Malignant degeneration --- squamous cell carcinoma, sarco- disease starts as a yellowish erythematous papule or nodule, mas, Hodgkin’s lymphoma --- has been reported in patients progressing to painful ulceration with irregular edges, infil- with long-term LV.7,35,39 trated base, with no tendency to scarring, causing marked The disease has a chronic course and, if left untreated, oropharyngeal dysphagia. will cause deformities due to the destruction of structures in the affected anatomical sites. Spontaneous healing of LV Histopathology is very difficult, but can occur after several years, leaving an atrophic or deforming scar. Ulceration of the lining epithelium and dermis and granu- lomas with caseation necrosis ---- there are numerous AFB, Histopathology demonstrated by special stains (Figs. 3B and 3C). The epidermis may present with atrophy, acanthosis, pseu- doepitheliomatous hyperplasia, or ulceration. In the dermis, 134 lesione rilevata e molle, giallastra o rossastra, chiamata lupoma, che evolve lentamente in una placca rosso violacea, a bordi irregolari e policiclici, a superficie cheratosica, che può raggiungere dimensioni notevoli, con graduale infossamento e cicatrizzazione della zona centrale e progressiva espansione dei margini. Alla vitropressione si osserva una colorazione giallastra (“a marmellata di mele”) alla periferia della lesione. L’estensione agli orifizi è responsabile di mutilazioni, atresie ed ectropion. In assenza di trattamento, l’evoluzione è lenta e mal definita. La lesione può essere complicata tardivamente da un carcinoma spinocellulare.  Anais Brasileiros de Dermatologia 2022;97(2):129---144 Figure 4 (A), Lupus vulgaris --- infiltrated, eroded lesion, with sharp edges, in the right masseteric region. (B), Lupus vulgaris --- extensive plaque covered with papules/nodules, scarring areas, with sharp raised edges on the right gluteal region. (C), Lupus vulgaris --- the dermis shows granulomatous inflammation with foci of caseous necrosis, (Hematoxylin & eosin, ×40). Figure 5 (A), Gummatous TB --- irregular ulcer with sharp edges on the cervical region. (B), Gummatous TB --- granuloma consisting of lymphocytes, macrophages and multinucleated giant cells, (Hematoxylin & eosin, ×100). tuberculoid granulomas containing Langhans-type multin- Differential diagnosis ucleated giant cells and surrounded by lymphocytes can be observed. Caseation necrosis is minor and sometimes The following should be included: lupus erythematosus, absent. AFB is difficult to identify or absent (Fig. 4C). sarcoidosis, cutaneous pseudolymphoma, leishmaniasis, lep- rosy, tertiary syphilis, paracoccidioidomycosis, and diseases with similar clinical expression. Diagnosis Acute miliary tuberculosis The diagnosis is carried out through the clinical appearance and diascopy of skin lesions, strong reactive PPD, culture in Acute miliary tuberculosis or disseminated cutaneous tuber- specific media, histopathological analysis, IGRA, PCR for M. culosis occurs by hematogenous spread of the active focus tuberculosis. of BK from visceral tuberculosis, commonly from the lungs. 135  LA GOMMA E’ IL NODULO CHE SI ULCERA, LO SCRUFULODERMA I NODULI CHE FISTOLIZZANO A.C. Brito, C.M. Oliveira, D.A. Unger et al. The higher prevalence is observed in childhood, in patients Histopathology immunosuppressed by HIV infection, undergoing chemother- apy, using immunosuppressants for autoimmune disease, and AFB is evidenced in areas of massive caseation necrosis. in transplant recipients. It represents a rare form of TB, Tuberculous panniculitis cases reveal granulomas with mult- however, with risk of death for this group of patients. Coin- inucleated giant cells, and AFB are demonstrated by special fection with HIV in patients with a CD4 cell count < 100/!L staining (Fig. 6B). has contributed to the increase in the number of cases of this clinical form of tuberculosis.8---12 Diagnosis Clinical manifestations PAPULE VESCICOLE CROSTE The diagnosis is attained through the clinical aspect of the lesions and laboratory support: bacilloscopy and culture for The lesions are polymorphic, including papules, vesicles, AFB, anatomopathological analysis, PPD, IGRA, PCR. pustules, nodules, with preferential distribution in the upper and lower limbs, and trunk, but they can be disseminated, usually asymmetric. Whitlow abscesses and ulcerations have Differential diagnosis been recorded in the literature.7---9 The following should be considered: panniculitis of other etiologies, NTM, deep mycoses (especially sporotrichosis), Histopathology syphilis. The histomorphological picture of the initial lesions shows areas of necrosis and neutrophilic abscesses. As the lesions Cutaneous tuberculosis after BCG vaccination progress, the presence of histiocytes and the formation (Bacillus Calmette-Guerin) of granulomas in the periphery of the infiltrate can be observed. Numerous AFB can be identified in neutrophilic The BCG vaccine was developed by Albert Léon C. Calmette abscesses, as well as vascular thrombi. and Jean M. Camille Guérin and used for the first time in 1921. It must be applied after birth until before the age of five, aiming to protect the individual against tuberculosis Diagnosis by preventing the primary infection caused by M. tubercu- losis from progressing, especially into severe forms of the It is based on the dermatological lesions, general physical disease --- meningoencephalitis and miliary tuberculosis. Vac- examination, bacilloscopy, culture in specific media, anato- cine protection is low in adults.17,41 The main hypothesis mopathological analysis, IGRA, PCR, diagnostic imaging. is that BCG induces effector memory T cells that will pro- tect the individual for 10 to 15 years. Another factor would be that the protective effect of the vaccine would suffer Differential diagnosis geographic variation.42 Approximately 12 vaccines against TB are under devel- The following should be considered: NTM, secondary opment: recombinant BCG (rBCG), Mycobacterium vaccae, acneiform syphilis, deep mycoses, sarcoidosis, drug reac- protein vaccines with adjuvants, viral vector vaccines, DNA tions. vaccines, RNA-based vaccines, and others.13,42 Adverse effects occur with any vaccine used in the world, and the BCG vaccine is no exception. The most frequently Gummatous tuberculosis detected adverse effects of the BCG vaccine include: sub- cutaneous cold abscess; suppurated regional lymph node Gummatous tuberculosis (GT) or metastatic tuberculous disease; ulceration with a diameter > 1 cm; keloid-type abscesses is a type of CTB caused by the hematoge- scars; Koch’s phenomenon; lupus vulgaris lesions (at or near nous spread of M. tuberculosis originating from a primary the vaccine site), scrofuloderma, tuberculid-like lesions; tuberculous focus.7---9,11,13,18 GT has a higher incidence in osteoarthritis. Exceptionally, generalized lesions affecting immunosuppressed individuals and in children and adoles- other organs have been recorded (Fig. 7).41,42 cents with malnutrition (Figs. 5A and 5B).7---9,17 Tuberculids Clinical manifestations Most recent studies do not consider tuberculids as authentic The initial lesions are firm nodules, progressing to abscesses forms of CTB, but rather a heterogeneous group of clinical and later ulceration, draining necrotic material, located on entities that result from the host’s hypersensitivity response the trunk and on the upper and lower limbs. Some lesions to M. tuberculosis. Bacilloscopy is usually negative for AFB mimic those seen in scrofuloderma. Tuberculous gumma in skin lesions. with a sporotrichoid appearance has been the subject of The main forms are papulonecrotic tuberculid, lichen several published studies that emphasize the difficulty in scrofulosorum (lichenoid tuberculid), and erythema indura- conclusively diagnosing these cases (Fig. 6A).7---11,16,40 tum of Bazin - nodular vasculitis. 136 QUINDI LO SCRUFOLODERMA E’ IL PROTOTIPO DELLA CONTIGUITA’. LA GOMMA LO E’ DELLA DIFFUSIONE EMATOGENA  Anais Brasileiros de Dermatologia 2022;97(2):129---144 Figure 6 (A), Sporotrichoid gummatous TB --- ulcerated lesions along the upper limb. (B), Sporotrichoid gummatous TB - numerous resistant acid-fast bacilli (AFB) in the infiltrate on Fite-Faraco staining. Pictures by: Dr. Deborah Unger. Papulonecrotic tuberculid Its association with pulmonary, extrapulmonary, tuber- culous mesenteric lymphadenopathy with reactive PPD has Papulonecrotic tuberculid (PNT) is currently a rare form of been reported.44 Evidence of the presence of AFB is diffi- the disease in industrialized countries; however, it is still cult to attain or it is absent in skin lesions. However, there common in developing countries with a high prevalence of are several studies that have identified the presence of M. tuberculosis. Children, adolescents, and young adults are tuberculosis DNA by PCR in 50% of PNT lesions.7,11,45 Pos- the main victims of this tuberculid variant.13,17,18,43 itive cultures for the microorganism are also reported in 137 PAPULE DERMICHE , POI PUSTOLE NECROTICHE CON CICATRICI ATROFICHE VARIOLIFORMI  PAPULE LICHENOIDI IN PLACCHE PERIFOLLICOLARI, GIALLE O ROSSO BRUNASTRE A.C. Brito, C.M. Oliveira, D.A. Unger et al. Lichenoid tuberculid or lichen scrofulosorum It is characterized by lichenoid papules in individuals highly sensitized to M. tuberculosis and/or its proteins. It is fre- quently associated with tuberculosis in the pleura, lungs, osteoarticular areas, lymph nodes, and other organs. Chil- dren and adolescents are the most frequently affected groups, usually from a tuberculous focus.16,17,36,46 Some stud- ies show the occurrence of this tuberculid post-vaccination with BCG, as well as infections by NTM, among which the M. avium-intracellulare complex stands out. However, M. tuberculosis DNA has been previously demonstrated by PCR in some cases.7,14,45 Clinical manifestations Asymptomatic lichenoid papular eruption, with greater concentration on the trunk. There are follicular and/or Figure 7 Post-BCG TVC --- disseminated annular lesions on the perifollicular papules, isolated or coalescent, forming trunk and upper limbs. plaques with slight scaling on the surface. Spontaneous or treatment-specific resolution may occur.46 skin lesions.45 The association of PNT with discoid lupus erythematosus, erythema nodosum, and arthritis have been Histopathology reported in the literature.13,43 The upper dermis reveals a granulomatous inflammatory infiltrate consisting of epithelioid cells, associated with a Clinical manifestations LESIONI A STAMPO small number of giant Langhans cells and scarce lympho- cytes, affecting hair follicles and sweat glands. In other This is a skin eruption that usually occurs in recurrent areas of the dermis, the lymphocytic inflammatory infiltrate outbreaks of erythematous papules that progress with cen- is perivascular, with a low density. Absence of M. tuberculo- tral necrosis and ulceration covered by crusts --- called sis on special staining of the biopsy material and in cultures punched-out lesions. The distribution of lesions is symmet- for AFB. In some studies, the presence of M. tuberculosis ric, preferably on the extension surfaces of the upper limbs has been demonstrated by PCR.45 (including hands), lower limbs, and the trunk. After treat- ment or spontaneous resolution, varioliform scars are the Differential diagnosis result (Figs. 8A and 8B). It necessarily includes lichen planus, lichen nitidus, sec- ondary lichenoid syphilis, papular sarcoidosis. Histopathology Ulcerated epidermis and dermis with an area of wedge- Erythema induratum of Bazin and nodular shaped necrosis and dense granulomatous chronic inflam- vasculitis matory infiltrate with few multinucleated giant cells in the surrounding connective tissue. Necrosis may affect hair folli- Ernest Bazin, a French dermatologist, was the first to cles and granulomatous vasculitis is the alteration detected describe this form of tuberculid in 1861, which was named in some cases (Fig. 8C). after him.7---11,17,47 Erythema induratum of Bazin (EIB) and nodular vasculitis (NV) are diseases included in the category of lobular pan- Diagnosis niculitis, whose clinical manifestations predominate in the lower limbs. The identification of M. tuberculosis DNA by The diagnosis is attained through the clinical picture PCR in skin lesions in some cases confirms the tuberculous and complementary exams: reactive PPD, histopathological etiology. The term nodular vasculitis or erythema induratum analysis and PCR for AFB. of Whitfield should be reserved for indurated erythema not associated with tuberculosis.47,48 Differential diagnosis Epidemiology The following should be considered: pityriasis lichenoides EIB and NV predominate in young and middle-aged females; et varioliformis acuta, leukocytoclastic vasculitis, secondary however, males can be affected, as well as any ethnic group. syphilis, prurigos. Countries with a high incidence of tuberculosis have a higher 138  Anais Brasileiros de Dermatologia 2022;97(2):129---144 Figure 8 (A), Papulonecrotic tuberculid --- ‘‘punched-out’’ lesions on the lower limbs. (B), Papulonecrotic tuberculid --- papuloery- thematous and papulocrustous lesions in the lower limbs. (C), Papulonecrotic tuberculid --- thinning of the epidermis and granulomas with caseation necrosis in the underlying dermis, (Hematoxylin & eosin, ×20). prevalence of these diseases and venous insufficiency is a Nodular vasculitis has been associated with several dis- frequent association. This variant is very rarely observed in eases: hepatitis B and C, rheumatoid arthritis, ulcerative children, although there are several case reports from South colitis, Crohn’s disease, leukemia, hypothyroidism. Some Africa and Pakistan. A case of EIB due to BCG vaccination has drugs are also associated with NV --- propylthiouracil, and been recorded.13,17 etanercept.13,16 Clinical manifestations Pathogenesis They are characterized by erythematous or erythematous- Tuberculosis-associated EIB is observed in populations with violaceous, painful, isolated, or clustered nodules forming a prevalence of mycobacterioses. In patients with a clinical a nodular plaque, which progresses into an ulcer that drains picture of EIB/NV, in which the agent responsible for the skin necrotic or necro-purulent material. The preferential loca- lesions is not identified through histopathology and culture, tion of the lesions is on the posterior surface of the lower it is mandatory to use PCR and specific primers for an accu- limbs (calf); however, other places can be affected: upper rate diagnosis. It is considered that most cases of EIB are limbs, face, gluteal regions, thighs, and feet. The ulcer has a type IV cell-mediated hypersensitivity reaction, consider- sharp, raised edges, an hemorrhagic background, crusts and ing that T lymphocytes, macrophages, and Langerhans cells an infiltrated base. Regression of the lesion with scarring participate in the process. Studies have shown a strongly and subsequent recurrence is observed in most cases. Reac- reactive PPD in these cases and high positivity on the IGRA tive PPD is observed in patients with a tuberculous focus test for M. tuberculosis. (Fig. 9A). 139  A.C. Brito, C.M. Oliveira, D.A. Unger et al. Figure 9 (A), Erythema induratum of Bazin --- erythematous-violaceous infiltrated nodule on the posterior aspect of the lower limb. (B), Erythema induratum of Bazin --- Lobular granulomatous panniculitis. (C), Erythema induratum of Bazin: Strong reaction to PPD skin test. Histopathology Diagnosis An incisional biopsy is recommended to include as It is based on the clinical manifestations and complementary much of the adipose tissue as possible, especially to tests: positive PPD, histopathological analysis, and PCR for analyze the involvement of the adipose lobe present M. tuberculosis DNA (Fig. 9C). in the material. Punch biopsies cannot obtain enough adipose tissue for a more accurate histopathological anal- Differential diagnosis ysis. Microscopic findings in EIB/NV are lobular or mixed It should include erythema nodosum, pancreatic panniculi- septal/lobular granulomatous panniculitis, with an inflam- tis, lipodermatosclerosis (sclerosing panniculitis), panniculi- matory infiltrate consisting of lymphocytes, epithelioid tis caused by alpha-1 antitrypsin deficiency, other types of histiocytes, plasmocytes, and Langhans-type multinucle- vasculitis, especially cutaneous polyarteritis nodosa, sar- ated giant cells. Other identified histological alterations coidosis, and subcutaneous Sweet syndrome. include adiponecrosis, areas of caseation necrosis, and vasculitis compromising adipose tissue arteries and veins. Fibrosis is observed in lesions with a long-term evolu- Diagnosis of cutaneous tuberculosis tion. In general, AFB are not identified on special stains (Fig. 9B). Mycobacterium tuberculosis direct test or bacilloscopy aims to detect the microorganism in smears of biological material 140  Anais Brasileiros de Dermatologia 2022;97(2):129---144 stained by special techniques, with the Ziehl-Neelsen tech- In CTB, the biological material to be analyzed can be nique being the most often employed in laboratories. There fresh tissue or embedded in paraffin. The general sensitivity is low positivity for BK, 50 kg of body diagnosis. RIPE weight); isoniazid (300 mg/day), pyrazinamide (1,500 to The tuberculin test is an intradermal inoculation of 2,000 mg/day); ethambutol (750 mg/day for < 50 kg body 0.1 mL, equivalent to 2TU (tuberculin unit) of a purified weight and 1,000 mg/day for > 50 kg body weight). protein derivative of M. tuberculosis (PPD-RT23, in Brazil) Doses for children: rifampicin (10---20 mg/kg daily), iso- on the anterior surface of the left forearm to assess the niazid (10---15 mg/kg daily), and pyrazinamide (30---40 mg/kg patient’s cell immune response. The reading is carried out daily). 48 to 72 and up to 96 hours after the application, which Doses of drugs used in the maintenance phase: rifampicin is performed with a specific millimeter ruler to measure (600 mg/day for adults and 10 mg/kg daily for children) the largest cross-sectional diameter of the induration. The and isoniazid (600 mg/day for adults and 10 mg/kg daily for patient is considered to be infected with BK when the children).36 patient has an induration ≥ 5 mm (Fig. 9). Surgical excision may be considered in refractory lesions to correct deformities in recalcitrant cases.50 Interferon-gamma release assay Tuberculid treatment follows the same regimens recom- mended for true TB. For EIB, a longer period of treatment is The IGRA test is used to identify individuals with latent M. recommended, such as the proposed maintenance of iso- tuberculosis infection (LTBI); to identify individuals more niazid for up to two years.50 Dapsone, potassium iodide, likely to have LTBI and/or higher risk of becoming ill; to and doxycycline have been reported as adjunctive treat- indicate the correct treatment; to notify patients who will ments to treat inflammation in EIB, whereas corticosteroids be treated for LTBI and to monitor the treatment of these or tuberculin protein at different dilutions are occasionally patients. used for desensitization.50 The treatment of lupus vulgaris One should consider that PPD has limitations, including with isoniazid alone has resulted in high cure rates.51 cross-reaction with NTM and with BCG vaccine; false- Some studies have reported an eventual paradoxical skin negative results in immunocompromised patients (e.g., HIV reaction in patients undergoing regular treatment for TB, positive); the possibility of error in the test induration particularly in anergic patients treated for miliary TB. Weeks measurement; the need for two or three readings after or months after starting the polychemotherapy, purulent 48---72---96 hours. swollen skin lesions appear, whose culture for M. tubercu- The target population of this test is HIV-positive patients, losis is generally positive, representing an immunological patients with renal failure undergoing hemodialysis, and phenomenon (and not bacterial resistance) that responds patients with rheumatoid arthritis and psoriasis on immuno- well to continued treatment. 7 biological therapy. Immunobiologicals and latent tuberculosis Tests available in Brazil: QuantiFERON-TB Gold Plus® (QTF-G) and T-SPOT.TB In immunocompetent individuals, the host’s natural defense system controls the initial infection caused by M. tuber- The PPD and IGRA tests must be used simultaneously to culosis; the carrier remains asymptomatic and develops detect LTBI. Note that these tests cannot differentiate LTBI latent tuberculosis. However, in the presence of dis- from active infection. eases or medications that lead to immunosuppression, Polymerase chain reaction (PCR) is a molecular technique such as immunobiologicals, latent tuberculosis can be that attains amplification of specific sequences of DNA and reactivated.52,53 RNA nucleic acids. It is an important tool in the genotyping Significant advances in the understanding of the of pathogens, in atypical lymphoid infiltrates of T cells, in pathogenesis of immune-mediated diseases allowed the the investigation of malignant neoplasm translocations, in development of new drugs called immunobiologicals, which addition to other clinical entities. revolutionized the therapeutic approach to several diseases, 141 2 RIPE 4 RI  A.C. Brito, C.M. Oliveira, D.A. Unger et al. such as psoriasis. In particular, the introduction of tumor that ‘‘the subject be made available for public consultation, necrosis factor-alpha inhibitors (anti-TNF$) constituted one with a preliminary recommendation in favor of the incor- of the most revolutionary advances in the treatment of this poration of rifapentine (Priftin® ) into the SUS, to be used group of diseases, as they were the first target in treat- together with isoniazid in the 3HP regimen, for the treat- ment. In addition to the observed efficacy, one of the great ment of individuals with latent Mycobacterium tuberculosis advantages of these agents is their safety profile in rela- infection (LTBI).61 tion to the absence of toxicity in target organs, such as nephro- or hepatotoxicity, characteristic of conventional systemic treatments. However, as the blocking occurs in the Financial support initial phase of the immunological cascade, this therapeu- tic class leads to a broader immune suppression, which is None declared. not as selective and, therefore, does not have such a strong immunological safety profile.54 Authors’ contributions TNF-$ is a cytokine that plays a central role in the estab- lishment and maintenance of the inflammatory response Arival Cardoso de Brito: Approval of the final version of against infections, being crucial for the formation of granu- the manuscript; design and planning of the study; draft- lomas, which represent an essential defense function against ing and editing of the manuscript; effective participation intracellular pathogens such as mycobacteria. Anti-TNF-$ in research orientation; intellectual participation in the therapy compromises the physiological immunoinflamma- propaedeutic and/or therapeutic conduct of the studied tory responses mediated by TNF-$ and may alter the cases; critical review of the literature; critical review of formation and maintenance of granulomas, leading to TB the manuscript. reactivation or spread.55 Clivia Maria Moraes de Oliveira: Approval of the final ver- In patients receiving anti-TNF-$ treatment, the relative sion of the manuscript; design and planning of the study; risk of TB infection ranges from 1.5% to 17%, being higher drafting and editing of the manuscript; effective partici- with anti-TNF-$ monoclonal antibody therapy (adalimumab pation in research orientation; intellectual participation in and infliximab) than with therapy with soluble TNF-$ recep- the propaedeutic and/or therapeutic conduct of the studied tor (etanercept).56,57 cases; critical review of the literature; critical review of the In an attempt to better seek the specific target to be manuscript. blocked in the treatment of autoimmune diseases, anti- Deborah Aben-Athar Unger: Approval of the final ver- interleukin immunobiologicals emerged, which are more sion of the manuscript; design and planning of the study; selective and, therefore, have a much better safety profile. drafting and editing of the manuscript; effective partici- It is possible that blocking anti-IL does not carry the same pation in research orientation; intellectual participation in risk of TB reactivation as TNF-$ inhibitors.58 Th17-related the propaedeutic and/or therapeutic conduct of the studied cytokines seem to contribute to immunological protection cases; critical review of the literature; critical review of the against primary M. tuberculosis infection, and their expres- manuscript. sion levels decrease in patients with TB.58 Maraya de Jesus Semblano Bittencourt: Approval of the Despite the effect on the defense mechanism against M. final version of the manuscript; design and planning of the tuberculosis infection of IL-17 and IL-23, the available safety study; drafting and editing of the manuscript; effective par- data on anti-IL-17 and anti-IL-23 immunobiologicals demon- ticipation in research orientation; intellectual participation strate that this effect may be lower than expected, and this in the propaedeutic and/or therapeutic conduct of the stud- may constitute an advantage of this group of immunobio- ied cases; critical review of the literature; critical review of logicals in relation to anti-TNF and anti-IL 12/23. However, the manuscript. further studies on the safety of anti-interleukin immunobi- ologicals are needed to further elucidate the issue.59 It is recommended by international guidelines that prior Conflicts of interest to treatment with immunobiological drugs, a careful TB investigation should be carried out.58 The investigation None declared. should be performed with the simultaneous use of PPD and IGRA and chest radiography (PA and profile), performed periodically.59 References Although PPD is a test to assess personal exposure to TB, in patients with psoriasis there is a possibility of false- 1. who.int [Internet]. Genebra: World Health Organization; positive results due to pathergy. A decreased response to c2021. Who operational handbook on tuberculosis: module 1: PPD occurs during treatment with methotrexate, making it prevention: tuberculosis preventive treatment. 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