Chapter 15: Tuberculosis in Adults
by Afranio Kritski and Fernando Augusto Fiuza de Melo
15.1. Introduction
Tuberculosis (TB) is a disease with deep social and economical roots. Low-income people with large families, living in dense urban communities with deficient housing conditions, have a high probability of becoming infected, developing active disease, and dying from TB. Also, the risk of becoming infected and ill with TB is higher among people that live in congregated institutions, such as prisons, youth correctional facilities, nursing homes for elderly people, social shelters, day nurseries and schools; the same is valid for elderly people, diabetics and people living with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) (Dye 1999, American Thoracic Society 2000, Castelo-Filho 2004, World Health Organization 2006).
The lung is the main entrance gate of the tuberculous bacillus, which causes a focal infection in the site where it is deposited after inhalation. If the infection cannot be contained at the local level, bacilli dissemination is produced initially by hematogenic route, probably inside phagocytic cells, towards different organs and, eventually, to the contiguous pleura. It reaches hilar lymph nodes via the lymphatic route, and from there, a second systemic dissemination can occur, through the thoracic duct and superior vena cava, with the development of local foci in the lungs. Extrapulmonary foci can also be produced by hematogenic and lymphatic dissemination. The clinical manifestations of TB depend on the local organic defenses on the sites of bacilli multiplication (Rich 1944, Bates 1980, Stead 1984). It has been emphasized that the use of bacille Calmette-Guérin (BCG) vaccination may play a role in this phase, avoiding dissemination and the occurrence of extrapulmonary forms of TB.
15.2. The initial lesion
Once inhaled, most tubercle bacilli are trapped in the mucosa of the upper respiratory tract, trachea and bronchi, especially when inhaled in clumps, and are eliminated by the mucocilliary defense mechanisms. Tiny particles or droplet nuclei smaller than 5 µm behave as a gas and overcome this barrier and reach the inferior respiratory tract, especially inside the alveoli, where they are readily phagocytosed by alveolar macrophages.
The survival of the infectious agent in the lung will depend on its pathogenicity/virulence and on the ability of the host cells to eliminate it. The alveolar macrophages are the first line of defense against Mycobacterium tuberculosis. This initial response, if completely effective, will cause the elimination of the pathogen through the phagocytic action inherent to such macrophages (see Chapter 5). If the alveolar macrophage is not capable of arresting bacterial growth, a localized pro-inflammatory response is formed through the activity of Toll-like receptor agonists, abundant on the surface of bacteria. Tumor necrosis factor alpha (TNF-a) and inflammatory chemokines produced by the infected macrophages recruit white blood cells, which phagocytose bacilli and eventually return to the bloodstream causing the primary hematogenic dissemination (Figure 15-1).
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Figure 15-1: Non-specific inflammation with blood white cell migration and primary hematogenic dissemination The recruited cells produce their own complement of chemokines and cytokines that amplify cellular recruitment and remodel the infection site into a cellular mass, the tubercle or granuloma. The granuloma initially formed consists of a core of infected macrophages surrounded by foamy macrophages, with an external layer of lymphocytes encircled by collagen and other extracellular matrix components (Russell 2007). Tubercle bacilli can disseminate by the lymphatic route to regional lymph nodes, constituting the tuberculous primary complex of Ranke, composed by the original granuloma at the inoculation site (Gohn’s nodule), the lymphangitis and the hilar lymph node enlargement (Figure 15-2). Although in some cases these lesions may become evident on chest X-ray, most cases of primary tuberculous infection are clinically and radiologically unapparent, with a positive TST being the only indication of the occurrence of the infection. Figure 15-2: Primary infection, inoculation lesion, primary complex, and initial TB dissemination From the hilar lymph nodes, tubercle bacilli disseminate to tracheal and vertebral lymph nodes. Through the thoracic duct, they reach the blood stream, spreading to the upper areas of the lungs or to different organs, such as kidney, brain, and bones. At these sites, they find a favorable atmosphere for implantation that combines a satisfactory oxygen tension and a low local perfusion: this is an ideal association that hinders the access of defense cells. 15.3. The inflammatory response With the development of specific cellular immune response and production of interferon-gamma (IFN-?), a mature stable granuloma is formed, which is responsible for the immune containment of the pathogen. Mature granulomas present neovascularization, epithelioid and giant multinucleated cells. An extensive fibrotic capsule develops and infected macrophages trapped inside granulomas eventually die. Tubercle bacilli tend to locate in the center of the granuloma, but bacteria and antigens are also associated with macrophages in the peripheral infiltrate (Russell 2007). The necrotic material present in the center of TB lesions contains high amounts of fat representing the lipids liberated from bacillary catabolism. This material, which has a soft, dry and cottage cheese texture, is known as caseous necrosis. On microscopy, large amounts of epithelioid and giant multinucleated cells can be observed in the granulomas, located mainly around the caseous material. The nature of the host immune response will determine whether the infection will progress or be contained. The discussion regarding the participation of T lymphocytes in the development of infectious diseases has lead to the paradigm, initially developed in the murine model, which characterizes CD4+ T lymphocytes in two subpopulations named T helper 1 (Th1) and T helper 2 (Th2). In the human infection, however, such a clear division into two different cytokine response patterns is not observed. Unlike the murine model, a wide spectrum of cytokines are produced in response to infection by M. tuberculosis in the human host, and their function in containing the infection is not yet completely understood (Chacon-Salinas 2005). Individuals who are able to mount an immune response adequate enough to contain M. tuberculosis bacilli at this stage will develop a clinical form of infection, characterized as latent infection, in which bacilli will stay for an undetermined period of time. The risk of progressing to clinical TB is highest during the first 3-5 years after the infection, especially among immunosuppressed individuals. In view of this, the disease can occur: · during the initial phase of infection – due to excessive bacillary load, increased bacterial pathogenicity/virulence and/or factors that decrease host immune response. In this case, a host-parasite balance is not achieved, which results in the development of primary TB a few months after the infection. · posterior to the initial phase of infection – due to a rupture of the host-parasite balance in individuals with latent TB, resulting in post-primary TB. 15.4. Tuberculosis infection In most individuals, TB infection is clinically irrelevant and seldom recognized. It commonly occurs during childhood (see Chapter 16), and may occasionally cause malaise, low-grade fever, erythema nodosum, and phlyctenular conjunctivitis. Erythema nodosum is a toxic allergic nodular lesion 2 to 3 cm large, located in or under the skin. These lesions are spontaneously painful and very painful under pressure, and are usually located bilaterally on the anterior surface of feet and legs. In most individuals, however, primary TB infection causes no apparent symptoms and the infection stays latent for life or until reactivation (Bates 1980, Melo 1993, Lima 1993). Chest X-rays can present several manifest ations. The classical presentation is known as the primary Ranke’s complex, including a calcified peripheral lung nodule (Gohn’s primary focus), lymph tracts toward the hilus (lymphangitis), and enlarged local lymph nodes (Figures 15-3 and 15-4). Figure 15-3: Chest X-ray showing a calcified peripheral nodule in the lower right lung (Gohn’s primary focus) (Reproduced from Melo 2005a) Figure 15-4: a: Chest X-ray showing a calcified peripheral nodule in the lower right lung, lymphangitis (encircled in b) and hilar involvement (Ranke’s complex) (Reproduced from Melo 2005a). In the initial phase of M. tuberculosis infection, some tubercle bacilli can reach the upper lobes of the lungs, creating small metastatic foci referred to as Simon foci, visible on chest X-ray (Figure 15-5). Figure 15-5: Simon nodule in upper lobe of the right lung in an asymptomatic adult. a and b: chest X-ray, c: computerized tomography. For additional images of TB infection see Presentation 1 at http://www.tuberculosistextbook.com/pdf/Presentation_1.pdf. 15.5. Tuberculosis disease The development of clinical TB will occur in 5 %-10 % of infected persons at some point in their lives, for reasons that are not completely clear. Some factors involved in increased risk of developing TB have been established, of which the most important are those interfering directly with host immunity. Diseases and conditions that weaken immunity, such as malnutrition, alcoholism, advanced age, HIV/AIDS, diabetes, gastrectomy, chronic renal insufficiency, silicosis, paracoccidioidomycosis, leukemias, solid tumors, immunosuppressive drug treatments, and hereditary features, are factors that facilitate the development of TB disease. Additional factors include the infective bacterial load, pathogenicity/virulence of bacilli, and host genetic susceptibility (ATS- 2000). 15.5.1. The primary disease Adult primary TB is paucibacillary, practically non-contagious, difficult to diagnose, and of variable severity, as described in children (see Chapter 16). In seriously immunodepressed patients, but also in individuals with IFN-? or IL-12 receptor deficiency, it can develop into a disseminated form, which is sometimes fatal. High morbidity in the primary form was also observed in patients whose ancestors were not previously exposed to the tubercle bacillus, as reported in the Yanomami Indians in the Amazon Region (SantŽAnna 1988, Souza 1997). For images of primary disease see Presentation 2 at http://www.tuberculosistextbook.com/pdf/Presentation_2.pdf. 15.5.2. The post-primary disease The existence of post-primary TB, also known as secondary TB, means that the infection can progress after the development of an adequate specific immune response. This TB episode can develop in two ways: by inhalation of new bacilli or by reactivation of the primary focus. Recently, in African countries, using molecular typing methods, it has been shown that the transmission is community driven, and not solely through households, and that reinfection with novel M. tuberculosis strains may occur in 40 % of relapsing cases (Verver 2005). The recurrence/relapse caused by new strains highlights the possibility that the progression to disease can be enhanced by multiple infections, especially among high-risk persons, such as HIV infected individuals. Pulmonary TB is the most common form of post-primary disease. Lymphatic dissemination can occur, but in this case the hilar lymph nodes are usually not affected. The response to bacillary multiplication provokes caseous necrosis that eventually blends and progresses to liquefaction. Tubercle bacilli, whose multiplication had been until then inhibited by granuloma formation, find favorable conditions for population growth after liquefaction of the caseum and subsequent cavitation, and may produce more than 108 bacilli per cavity with a diameter of less than 2 cm. The development of tuberculous cavities in the lung characterizes the post-primary TB and, from this lesion, infectious material can spread through bronchi, resulting in the continuous production and elimination of sputum. The natural evolution of post-primary lesions in immunocompetent persons can lead to dissemination and death in about 50 % of cases, and to chronicity in about 25 % to 30 %. Natural cure can also occur in 20 % to 25 % of cases, when the host immune response is able to re-establish control of the disease (Bates 1980, Melo 1993). In most non-immunosuppressed persons infected by the tubercle bacillus, disease will occur in the first three to five years after the initial exposure. In HIV positive persons infected with the tubercle bacillus, however, 7 % to 10 % will develop active TB annually (ATS 2000). The remaining cases occur at any time during a lifetime, especially when there are other diseases or weakening conditions, for example malnutrition, diabetes, prolonged treatment with corticosteroids, immunosuppressive therapy, chronic renal disease, gastrectomy, and others. The post-primary disease presents a great spectrum of manifestations, which are related to the affected organ. The lungs are most commonly affected, usually in the upper lobes or apical segments of inferior lobes. The disease can also affect other organs, including lymph nodes, pleura, kidneys, the central nervous system, and bones. In pulmonary TB, the patients often present with an insidious clinical onset, sometimes with minimal or non-specific complaints in the initial phase. With the development of the disease, two types of signs and symptoms can be recognized. The most frequent are: lack of appetite, low-grade evening fevers, and night sweats. Additional symptoms are asthenia, irritability and migraine. With respect to respiratory signs and symptoms, the patient may complain of cough of insidious evolution, at any hour of the day, which as initially dry and later on productive with purulent or mucous expectoration. Hemoptysis and bloody sputum occur in less than a quarter of patients, with the worst cases originating from lesions invading blood vessels. Chest pain can be localized and dependent on breathing movements (Hopewell 2006). At the beginning of the disease, lung auscultation is of little help. Few crackles can be noticed on auscultation after deep inspiration and also ronchi and tubular sounds. In most cases, the patient may be symptomatic for one to three months before diagnosis. Such delays in diagnosis may be due to low diagnostic suspicion by the medical personnel, lack of access to health services, because the patient may not acknowledge being sick or may not seek medical help due to economic or cultural reasons. An early diagnosis is critical for controlling transmission of the disease in the community, especially in congregated institutions, such as hospitals, prisons, and shelters. It is crucial to perform the diagnosis in the initial phase of this type of presentation in patients with recent symptoms (less than four weeks) (Figure15-6). If diagnosis is delayed, the disease may evolve rapidly, destroying the pulmonary parenchyma (Figures 15-7 and 15-8). The parenchymal infiltrates from post-primary TB in adults resemble a pyramid, with the base towards the lung periphery and the apex looking at the hilar area. In the past, it was recognized as a sign of the tubercle bacilli seeking a route for airborne dissemination (Figure 15-7). Figure 15-6: Parenchymal infiltrate in the upper left lung, in posteroanterior (a and b) and lordotic position (c). Figure 15-7: Lung infiltrate and cavitation in the upper lobe of the right lung. a and b: chest X-ray, c: computerized tomography (Reproduced from Melo 2005b). Figure 15-8: Chest X-ray showing parenchymal infiltrate and cavitation in the right upper lobe (a) and in both upper lobes (b) (Reproduced from Melo 2005b). For additional images of post-primary disease see Presentation 3 at http://www.tuberculosistextbook.com/pdf/Presentation_3.pdf. Sometimes, patients with acquired multidrug resistant TB (MDR TB), after several treatment schemes with available anti-tuberculosis medication, need to be submitted to thoracostomy, as shown in Figure 15-9. After achieving cure, respiratory symptoms such as a productive cough persist in some patients for several years. When the patient refers to recurrent hemoptysis with elimination of more than 15-50 mL of sputum per day, bronchiectasis and/or a fungus ball may be present (Figure 15-10). Figure 15-9: Patient with MDR TB showing sequelae resulting from chronic disease and thoracostomy. Figure 15-10: Chest X-ray showing fibrotic infiltrate and cavity with a fungus ball in the upper left lobe. For additional images of sequela of TB see Presentation 4 at http://www.tuberculosistextbook.com/pdf/Presentation_4.pdf. 15.5.3. Extrapulmonary tuberculosis After penetration into the organism through the respiratory route, M. tuberculosis can settle and multiply in any organ during the primary infection, before development of the specific immune response. After this, tubercle bacilli can multiply at any time when there is a decrease in the host’s immune capacity to contain the bacilli in their implantation sites. The specific signs and symptoms will depend on the affected organ or system, and are characterized by inflammatory or obstructive phenomena. Systemic symptoms are much less frequent than in pulmonary TB, except in the disseminated form of the disease. The majority of the extrapulmonary forms of TB affect organs with suboptimal conditions for bacillary growth. For this reason, the extrapulmonary disease generally has an insidious presentation, a slow evolution and paucibacillary lesions and/or fluids. Access to the lesions through secretions and body fluids is not always possible, and for this reason, invasive techniques may be necessary in many cases, to obtain material for diagnostic investigation. Tissues and/or body fluids should be submitted to laboratory examination, in particular bacteriological culture for mycobacteria and histopathological analysis. In the immunocompetent patient, the TST response is usually positive (induration = 10 mm). Imaging studies provide valuable information for the diagnosis of extrapulmonary TB, although specific radiological patterns are not observed. In immunocompetent patients, the extrapulmonary forms only occasionally coexist with active pulmonary TB. Nevertheless, the chest X-ray is mandatory for the evaluation of evidence of primary infection lesions, which provide a good verification to support the diagnosis (Rottenberg 1996). Miliary tuberculosis Miliary TB results from the massive hematogenic dissemination of the Koch bacillus during the primary infection. Its onset may be either insidious or abrupt, depending on the bacillary load and/or the host immune situation, with unvaccinated infants, elderly and immunodeficient patients being the most susceptible (Lester 1980, Thornton 1995). The variable and often nonspecific symptoms include fever, anorexia, weight loss, and asthenia. Other specific symptoms depend on the organs affected, and involvement of the central nervous system occurs in 30 % of cases. The physical examination is unspecific, and the patient can present with variable degrees of wasting, fever, tachycardia and toxemia. The observation of bacilli on smear microscopy examination is rare, and culturing mycobacteria provides a higher probability of bacteriological confirmation of the diagnosis of TB. In the advanced stages of HIV/AIDS (CD4+ cell count lower than 200 cells/mm3 or peripheral blood lymphocyte count lower than 1000/mm3), the bacilli circulate in the bloodstream, and tubercle bacilli are often isolated from blood when appropriate culture media are used (see Chapter 17). Chest X-ray shows a characteristic diffuse, bilateral and symmetrical micronodular infiltrate (Figure 15-8). Other characteristic TB lesions can be found simultaneously, such as cavities, focal parenchymatous condensations, and pleural effusion. Bilateral involvement is highly suggestive of miliary dissemination. Mediastinal and hilar lymphadenopathy appear more frequently in patients with recent lung infection (primary TB) or HIV co-infection (Figure 15-11). The diagnosis of TB can also be obtained when caseous granuloma is found in biopsy material (Lester 1980, Thornton 1995). Figure 15-11: Miliary pattern of primary TB in adults. a and b: chest X-ray, c: computerized tomography. Pleural tuberculosis This is the most common form of extrapulmonary TB, and can either result from the rupture of a primary sub-pleural lung focus (evident or not on conventional chest X-ray) or be secondary to lymphohematogenic dissemination. The presence of a pleural TB effusion has also been related to hypersensitivity (Light 1990). Most cases occur several months after the primary infection, and frequently the patient relates having contact with an active pulmonary TB case in the two years preceding the current episode. The simultaneous presence of active pulmonary TB may be related to recent infection followed by disease. The onset of the disease may be insidious or abrupt, with fever, systemic complaints, dyspnea, dry coughs, and pleuritic thoracic pain. The physical examination shows signs characteristic of pleural effusion. With regard to diagnosis, the result of the TST may be negative at the diagnosis of the disease and become positive during anti-tuberculosis treatment. The pleural effusion is generally unilateral and moderate, and can easily be detected by conventional chest X-ray examination (Figure 15-12). In one third of cases, an underlying lung infiltrate can be observed. Figure 15-12: Pleural involvement with no parenchymal lesion (a) and with upper lobe lung infiltrate (b). Thoracocentesis and puncture pleural biopsy should be indicated. The pleural liquid has a typically citrine yellow aspect and sometimes may be sero-hemorrhagic. It is generally an exudate with a predominance of lymphomononuclear cells, often negative for acid-fast bacilli (AFB) on microscopic examination. The etiological diagnosis is confirmed by the isolation of M. tuberculosis by culture of the fluid. The histopathological finding of granulomatous lesions in the pleural biopsy also confirms diagnosis, especially in countries with a high TB prevalence (Light 1990, Uehara 1993). An important auxiliary method in the diagnosis of pleural TB is the determination of adenosine deaminase (ADA), an enzyme liberated by activated lymphocytes. This examination has a sensitivity and specificity above 90 %. Thus, ADA activity above the cut-off level in the pleural liquid is highly suggestive of pleural TB. If the patient is below 45 years of age and the pleural liquid shows predominance of lymphomonocytic cells, the specificity and positive predictive value of ADA may approach 100 % (see Chapter 12). The differential diagnosis for pleural effusions includes para-pneumonic pleural effusions, mycoses, malignant diseases, and, especially in young women, collagen vascular diseases. Most of the time, the effusion is resolved, even if not treated, leaving minimal or no radiological sequelae. Nevertheless, there is a high risk of reactivation of pulmonary TB in the following years if pleural TB is not adequately treated with anti-tuberculosis drugs (Light 1990, Uehara 1993). Lymph node tuberculosis This is the second most common form of extrapulmonary TB in HIV seronegative patients and the most frequent in patients living with HIV/AIDS. The preferential localization is the anterior cervical lymph node chain with little predominance of the right side chain. Initially, lymph nodes grow slowly, and are painless and mobile. Later on, as their volume increases, they tend to coalesce and some develop fistulas (Figure 15-13). Patients mainly complain of fever and the increasing volume of lymph nodes, but other symptoms may be absent. In general, the TST is strongly positive, except in immunosuppressed patients. Figure 15-13: Lymph node TB in cervical area. The images are similar to those described in primary TB in children: enlargement of hilar and mediastinal lymph nodes (Figure 15-14). The etiological diagnosis can be made by aspiration puncture biopsy, which is AFB positive in only 10 % to 25 % of cases, but M. tuberculosis may be isolated by culture in 50 % to 85 % of cases. Cytopathology may be suggestive of the disease if there is a high proportion of Langhans cells. The histopathological analysis of the lymph node biopsy is usually conclusive, showing granuloma with caseous necrosis in 91 % to 96 % of cases (Lester 1980, Light 1990, Kang’ombe CT 2004, Greco 2004). Figure 15-14: Enlargement of left hilar lymph node in an HIV-infected patient. a and b: chest X-ray, c: computerized tomography. Renal tuberculosis Renal TB is rare in children and predominantly affects individuals in the fourth decade of life. Renal disease occurs after a long latency period and is frequently secondary to hematogenous dissemination. The localization is almost always bilateral, but can be asymmetric. The lesions often start in the renal cortex and progress slowly toward the central region. Dissemination can occur to the bladder and even to the genital system. Symptoms and signs may vary in duration and severity. The patient generally complains of dysuria, polacyuria, and lumbar pain, whereas systemic symptoms occur less frequently. Frequently, the disease presents as a urinary infection that does not respond to routine broad spectrum antimicrobial treatment. Purulent urine is frequently found, with urine culture negative for common germs (aseptic pyuria). Hematuria occurs in 10 % to 15 % of the cases. Excretory urography can either be normal or present a wide variety of alterations that include parenchymatous cavities, dilatation of the pyelocalicial system, renal calcifications of irregular contours, decreased capacity of the urinary bladder, and multiple ureter stenoses (Figure 15-15). Due to the high association between renal TB and urinary bladder TB, cystoscopy is indicated. In the cystoscopy, edema and diffuse hyperemia are observed, which are more intense around the orifice (golf hole sign), often accompanied by irregular ulcerations and/or infiltrates and vegetations. In these cases biopsy is indicated (Wise 2003). Figure 15-15: Infertility patient hysterosalpingogram, revealing proximal dilatations of the fallopian tubes (“rigid pipe stem” appearance ) and distal enlargments/constrictions (“beaded” appearance). Association with antecedents of anterior contagion with TB and TST = 22 mm, allowed the establishment of the diagnosis of TB salpingitis The diagnosis is confirmed when the urine culture is positive for M. tuberculosis. Culture of three to six specimens of first morning urine are together as reliable as the culture of a single 24-hour urine sample. TST is generally positive, except in patients with HIV/AIDS (Smith 1994, Simon 1977, Wise 2003). Tuberculosis of the central nervous system The compromise of the central nervous system occurs in two basic forms: meningoencephalitis and intracranial tuberculoma. Since the introduction of modern chemotherapy and especially massive BCG vaccination, a lower proportion of the meningoencephalitis has been observed, but the frequency of this form of TB is higher among young adults with HIV/AIDS (see chapter 17, Simon 1977, Smith 1994). The clinical manifestations are due to the inflammatory process induced by the mycobacterial infection, and the symptoms depend on the site and intensity of inflammation. Granulomas can be located in the cerebral cortex or in the meninges. Meningoencephalitis generally has an insidious onset and a slowly progressive course, with symptoms including apathy, lethargy, fever, and mental disturbances such as irritability, understanding difficulties, personality alterations, disorientation, and progressive mental confusion. Vertigo, migraine and vomiting can also be observed. Findings on physical examination are related to the stage of the disease and the affected area, such as cranial nerve involvement (the most affected are the 2nd , 3rd , 4th, and 8th nerve pairs), focal neurological deficits, and signs of meningeal and cerebellar irritation. The cerebrospinal fluid is generally clear, with a predominance of lymphocytes, an increase in proteins and a decrease in glucose levels. Microscopic examination for AFB is generally negative and cultures are positive in only 15 % to 30 % of cases. In the differential diagnosis the following conditions should be considered: other infectious meningitis, vascular pathologies, the collagen vascular disease sarcoidosis, metastatic carcinoma, acute hemorrhagic leucoencephalopathy, and lymphoma. In the case of intracranial tuberculoma, the clinical manifestations depend on the location of the lesion, which generally grows slowly. When there is no compromise of the sub-arachnoid space, the cerebrospinal fluid is normal and the computerized tomography exhibits a mass, which is generally difficult to differentiate from neoplasia (Azambuja 1993, Kasik 1994, Norris 1995). Figure 15-16: Computerized tomography of the skull in young adult patient with cerebral TB, with hydrocephaly, hypodense central areas, and atrophic lesions. Osteoarticular tuberculosis Involvement of the osteoarticular system is most commonly found in children and the elderly, and is generally secondary to hematogenous seeding, but can also occur as a consequence of lymphatic dissemination or direct spread from a contiguous lesion. Bone involvement consists of osteomyelitis, and arthritis can occur either by extension of the osseous lesion to the joint or by direct hematogenic inoculation. The most frequent sites of bone involvement are the vertebrae (Pott’s disease) and the proximal extremities of the long bones. Spinal TB frequently affects more than one vertebra. With evolution, it presents a wedged flattening and gibbus formation that can be associated with a paravertebral cold abscess (Figure 15-17). Paresthesia and paraplegia are reported when the cervical and upper thoracic area are affected. Image on X-ray is characterized by erosion of the anterior vertebral body margins with no preservation of the intervertebral space. The definitive diagnosis should be obtained by biopsy for culture and histopathological analysis (Ridley 1998, Schlesinger 2005). The peripheral joints most frequently affected by TB are the hip and the knee. Pain, with or without movement limitation, fever and systemic symptoms are frequent. Monoarticular involvement is much more frequent than multiarticular disease. The diagnosis of osteoarticular TB is usually delayed because this etiology is often overlooked in the differential diagnosis of joint disease. In most cases, the TST is positive, and approximately 50 % of cases also have abnormal chest X-rays, suggesting previous pulmonary disease. Cold abscesses occurring in the advanced phase of osteoarticular TB can develop into cutaneous fistulae, which are frequent in this form of the disease. The diagnosis is established by puncture, biopsy, histopathological examination, and culture (Zylbersztejn 1993, Davidson 1994, Ridley 1998, Schlesinger 2005). Other extrapulmonary localizations Tuberculous involvement of other tissues, such the eye, skin (lupus vulgaris), genital, and digestive tract, may also be the result of hematogenous dissemination, but there are other possible routes of infection. Intestinal TB can be acquired by the oral route, and in countries with a high prevalence of bovine TB. Before the generalization of milk pasteurization, this was a rather common form of zoonotic TB (produced by Mycobacterium bovis), particularly in infants. Figure 15-17: X-ray (a), computerized tomography scan (b), nuclear magnetic resonance (c), and scintilography (d) showing images of spondylitis and meningocele in a patient with PottŽs disease (from the archives of Instituto Clemente Ferreira, Brazil) Eye and skin TB may be the consequence of accidental inoculation, particularly among medical and veterinary professionals, and genital TB may be produced by spread from renal TB. 15.5.4. Special conditions During the past few decades, TB has been