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1357 Section 8 Mycobacterial Diseases 178 Tuberculosis Mario C. Raviglione, Andrea Gori Tuberculosis (TB), which is caused by bacteria of the Mycobacterium tuberculosis complex, is one of the oldest diseases known to affect humans and the top cause of infectious death worldwide excluding COVID-1...

1357 Section 8 Mycobacterial Diseases 178 Tuberculosis Mario C. Raviglione, Andrea Gori Tuberculosis (TB), which is caused by bacteria of the Mycobacterium tuberculosis complex, is one of the oldest diseases known to affect humans and the top cause of infectious death worldwide excluding COVID-19. Population genomic studies suggest that M. tuberculosis may have emerged ~70,000 years ago in Africa and subsequently disseminated along with anatomically modern humans, expanding globally during the Neolithic Age as human density started to increase. Progenitors of M. tuberculosis are likely to have affected prehominids. This disease most often affects the lungs, although other organs are involved in up to one-third of cases. If properly treated, TB caused by drug-susceptible strains is curable in the vast majority of cases. If untreated, the disease may be eventually fatal in over 70% of people. Transmission usually takes place through the airborne spread of droplet nuclei produced by patients with infectious pulmonary TB. Through pharmacological prophylaxis the development of the disease can be prevented in those who have contracted TB infection. FIGURE 178-1 Acid-fast bacillus smear showing M. tuberculosis bacilli. (Courtesy of the Centers for Disease Control and Prevention, Atlanta.) content (65.6%) is indicative of an aerobic “lifestyle.” A large proportion of genes are devoted to the production of enzymes involved in cell wall metabolism. Substantial genetic variability exists among the innumerable M. tuberculosis strains from different parts of the world. Based on such genetic variability it is possible to distinguish and compare different strains. Their distinction is important to study transmission dynamics and identify outbreaks. Starting in the 1990s, reproducible genotyping methods were developed to type the bacterium. Initially, they included insertion sequence 6110 (IS6110), restriction fragment length polymorphism (RFLP) typing, and spoligotyping. Lately, most studies utilize mycobacterial interspersed repetitive unit variable number tandem repeats (MIRU-VTNRs) and whole genome sequencing analysis. EPIDEMIOLOGY In 2019, 7.1 million new cases of TB (all forms, both pulmonary and extrapulmonary) were reported to the World Health Organization (WHO) by its member states; 97% of cases were reported from lowand middle-income countries. However, because of insufficient case detection and incomplete notification, reported cases represent only about two-thirds of the total estimated cases. The WHO estimated that 10 million (range 9-11 million; rate 130 per 100,000 people) new (incident) cases of TB occurred worldwide in 2019, 97% of them in low- and middle-income countries of Asia (6.1 million), Africa (2.4 million), the Middle East (0.8 million), and Latin America (0.28 million). Eight countries accounted for two-thirds of all new cases: India, Indonesia, China, the Philippines, Pakistan, Nigeria, Bangladesh, and South Africa. Of all cases, 57% occurred in male patients, 32% in female patients, and 11% in children. It is further estimated that 1.4 million (range, 1.3–1.6 million) deaths from TB, including 0.21 million among people with HIV co-infection, occurred in 2019; 98% of these deaths were in low- and middle-income countries. Estimates of TB incidence rates (per 100,000 population) and numbers of TB-related deaths in 2018 are depicted in Figs. 178-2 and 178-3, respectively. During the CHAPTER 178 Tuberculosis ETIOLOGIC AGENT Mycobacteria belong to the family Mycobacteriaceae and the order Actinomycetales. Of the pathogenic species belonging to the M. tuberculosis complex, which comprises eight distinct subgroups, the most common and important agent of human disease by far is M. tuberculosis (sensu stricto). A closely related organism isolated from cases in West, Central, and East Africa is M. africanum. The complex includes some zoonotic members, such as M. bovis (the bovine tubercle bacillus— characteristically resistant to pyrazinamide, once an important cause of TB transmitted by unpasteurized milk, and currently responsible for 140,000 human cases worldwide in 2019, half of them in Africa) and M. caprae (related to M. bovis). In addition, other organisms that have been reported rarely as causing TB include M. pinnipedii (a bacillus infecting seals and sea lions in the southern hemisphere and recently isolated from humans), M. mungi (isolated from banded mongooses in southern Africa), M. orygis (described in oryxes and other Bovidae in Africa and Asia and a potential cause of infection in humans), and M. microti (the “vole” bacillus, a less virulent organism). Finally, M. canetti is a rare isolate from East African cases that produces unusual smooth colonies on solid media and is considered closely related to a supposed progenitor type. There is no known environmental reservoir for any of these organisms. M. tuberculosis is a rod-shaped, non-spore-forming, thin aerobic bacterium measuring 0.5 μm by 3 μm. Mycobacteria, including M. tuberculosis, are often neutral on Gram’s staining. However, once stained, the bacilli cannot be decolorized by acid alcohol; this characteristic justifies their classification as acid-fast bacilli (AFB; Fig. 178-1). Acid fastness is due mainly to the organisms’ high content of mycolic acids, long-chain cross-linked fatty acids, and other cell-wall lipids. Microorganisms other than mycobacteria that display some acid fastness include species of Nocardia and Rhodococcus, Legionella micdadei, and the protozoa Isospora and Cryptosporidium. In the mycobacterial cell wall, lipids (e.g., mycolic acids) are linked to underlying arabinogalactan and peptidoglycan. This structure results in very low permeability of the cell wall, thus reducing the effectiveness of most antibiotics. Another molecule in the mycobacterial cell wall, lipoarabinomannan, is involved in the pathogen–host interaction and facilitates the survival of M. tuberculosis within macrophages. The complete genome sequence of M. tuberculosis comprises 4.4 million base pairs, 4043 genes encoding 3993 proteins, and 50 genes encoding stable RNAs; its high guanine-plus-cytosine 1358 Incidence per 100,000 population per year 0–9.9 10–99 100–199 200–299 300–499 ≥500 No data Not applicable PART 5 FIGURE 178-2 Estimated tuberculosis (TB) incidence rates (per 100,000 population) in 2018. The designations used and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization (WHO) concerning the legal status of any country, territory, city, or area or of its authorities or concerning the delimitation of its frontiers or boundaries. Dotted, dashed, and white lines represent approximate border lines for which there may not yet be full agreement. (Reproduced with permission from Global Tuberculosis Report 2019. Geneva, World Health Organization; 2019.) Infectious Diseases late 1980s and early 1990s, numbers of reported cases of TB increased in high-income countries after years of decline. These increases were related largely to immigration from countries with a high incidence of TB; the worldwide spread of the HIV epidemic; social problems, such as increase in urbanization and the related increased urban poverty, homelessness, and drug abuse; and dismantling of TB services. During the past few years, numbers of reported cases have begun to decline again or have stabilized in most industrialized nations. In the United States, with the re-establishment of stronger control programs, the decline resumed in 1993, and during the period 2007−2012, the decline rate was 6.5% annually on average. Later, between 2012 and 2019 this annual rate slowed down to 2.1%. In 2019, 8920 cases of TB Mortality per 100,000 population per year 0–0.9 1–4.9 5–19 20–39 ≥40 No data Not applicable FIGURE 178-3 Estimated tuberculosis (TB) mortality rates in HIV-negative people in 2018. (See disclaimer in Fig. 178-2. Reproduced with permission from Global Tuberculosis Report 2019. Geneva, World Health Organization; 2019.) WHO published the following new definitions: (i) Pre-XDR-TB, as TB caused by Mycobacterium tuberculosis strains that fulfill the definition of MDR/RR-TB and that are also resistant to any fluoroquinolone. (ii) XDR-TB, as TB caused by Mycobacterium tuberculosis strains that fulfill the definition of MDR/RR-TB and that are also resistant to any fluoroquinolone and at least one additional Group A drug including levofloxacin or moxifloxacin, bedaquiline and linezolid.) About 6.2% of the MDR-TB cases worldwide may be XDR-TB, but the vast majority of XDR-TB cases remain undiagnosed because reliable methods for DST are lacking and laboratory capacity is limited mainly in low-income countries. Lately, a few cases deemed resistant to all anti-TB drugs have been reported; however, this information must be interpreted with caution because susceptibility testing for several second-line drugs is neither accurate nor reproducible. ■ FROM EXPOSURE TO INFECTION M. tuberculosis is most commonly transmitted from a person with infectious pulmonary TB by droplet nuclei containing M. tuberculosis bacteria, which are aerosolized by coughing, sneezing, or speaking. The tiny droplets dry rapidly; the smallest (<5–10 μm in diameter) may remain suspended in the air for several hours and may reach the terminal air passages when inhaled. There may be as many as 3000 infectious nuclei per cough. Other routes of transmission of tubercle bacilli (e.g., through the skin or the placenta) are uncommon and of no epidemiologic significance. The risk of transmission and of subsequent acquisition of M. tuberculosis infection is determined mainly by exogenous factors, although endogenous factors may also play a role. The probability of contact with a person who has an infectious form of TB, the intimacy and duration of that contact, the degree of infectiousness of the case, and the shared environment in which the contact takes place are all important determinants of the likelihood of transmission. Several studies of close-contact situations have clearly demonstrated that TB patients whose sputum contains AFB visible by microscopy (sputum smear–positive cases) are the most likely to transmit the infection. The most infectious patients have cavitary pulmonary disease or, much less commonly, laryngeal TB and produce sputum containing as many as 105–107 AFB/mL. Patients with sputum smear–negative/culture-positive TB are less infectious, although they have been responsible for up to 20% of transmission in some studies in the United States. Those with culture-negative pulmonary TB and extrapulmonary TB are essentially noninfectious. Because persons with both HIV infection and TB are less likely to have cavitations, they may be less infectious than persons without HIV co-infection. Crowding in poorly ventilated rooms is one of the most important factors in the transmission of tubercle bacilli because it increases the intensity of contact with a case. The virulence of the transmitted organism is also an important factor in establishing infection. Endogenous factors such as the degree of immune competence are also important. In particular, HIV-infected patients, persons undergoing cancer treatment, or those administered immunosuppressive drugs may be at higher risk of TB infection acquisition. Because of delays in seeking care and in making a diagnosis, it has been estimated that, in high-prevalence settings, up to 20 contacts (or 3–10 people per year) may be infected by each AFB-positive case before the index case is diagnosed. Attempts to estimate the basic reproductive number R0 for TB have resulted in a wide range of values depending on environmental conditions and social behaviors of populations: from 0.24 in the Netherlands during the period 1933−2007 to 4.3 in China in 2012 reflecting the status of disease control. ■ FROM INFECTION TO DISEASE Unlike the risk of acquiring infection with M. tuberculosis, the risk of developing disease after being infected depends largely on endogenous factors, such as the individual’s innate immunologic and nonimmunologic defenses and the level at which the individual’s cell-mediated immunity is functioning. Clinical illness directly following infection is classified as primary TB and is common among children in the first few years of life and among immunocompromised persons. Although primary TB may be severe and disseminated, it generally is not associated 1359 CHAPTER 178 Tuberculosis (2.7 cases/100,000 population) were preliminarily reported to the U.S. Centers for Disease Control and Prevention (CDC). In the United States, TB is uncommon among young white adults of European descent, who have only rarely been exposed to M. tuberculosis infection during recent decades. In contrast, because of a high risk of transmission in the past, the prevalence of M. tuberculosis infection is relatively high among elderly whites. In general, adults ≥65 years of age have the highest incidence rate per capita and children <14 years of age the lowest. Among U.S.-born persons, African Americans accounted for the highest proportion of cases (35%; 905 in 2019), followed by white persons (756 cases), and Hispanic/Latinos (628). TB in the United States is also a disease of adult members of the HIV-infected population (4.9% of all cases), the foreign-born population (71% of all cases in 2019), and disadvantaged/marginalized populations. Of the 6322 cases reported among non-U.S.-born persons in the United States in 2019, 33% occurred in Hispanic/Latinos and 47% in persons born in Asia. Overall, the highest rates per capita were among nonU.S.-born Asians (26 cases/100,000 population) and native Hawaiian/ Pacific Islanders (25 cases/100,000 population). A total of 515 deaths was caused by TB in the United States in 2017. In Canada, TB cases and rates per 100,000 population have been increasing between 2014 and 2017 (from 1615/4.5 to 1796/4.9). In 2017, 1796 TB cases were reported (4.9 cases/100,000 population); 72% (1290) of these cases occurred in foreign-born persons, and 17.4% (313 cases) occurred in Canadian-born Indigenous Peoples, whose per capita rate is disproportionately high (21.5 cases/100,000 population). The highest rate was found in the territory of Nunavut, at 265 cases/100,000 population—a rate similar to that in many highly endemic countries. Similarly, in Europe, TB has reemerged as an important public health problem, mainly as a result of cases among immigrants from high-incidence countries and among marginalized populations, often in large urban settings such as London. In 2018, 36% of all cases reported from England occurred in London, 82% of them among people born abroad; although decreasing, the rate per capita (19 cases/100,000 population) is twice as high as that of England with a borough (Newham) reaching 47 cases per 100,000 population. Likewise, in most Western European countries, there are more cases annually among foreign-born than native populations. Recent data on global trends indicate that in 2019 the TB incidence was stable or falling in most regions; this trend began in the early 2000s and appears to have continued, with an average annual decline of 1.7% globally and 2.3% between 2018 and 2019. This global decrease is explained largely by the reduction in TB incidence in sub-Saharan Africa, where rates had risen steeply since the 1980s as a result of the HIV epidemic and the lack of capacity of health systems and services to deal with the problem effectively, and, less so, in Eastern Europe, where incidence increased rapidly during the 1990s because of a deterioration in socioeconomic conditions and the health care infrastructure (although, after peaking in 2001, incidence in Eastern Europe has since declined slowly). Of the estimated 10 million new cases of TB in 2019, 8.2% (0.82 million) were associated with HIV co-infection, and 73% of these HIV-associated cases occurred in Africa. An estimated 0.21 million persons with HIV-associated TB died in 2019. Furthermore, an estimated 465,000 (range 400,000-535,000) cases of rifampin- (also called rifampicin) resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB)—a form of the disease caused by bacilli resistant at least to isoniazid and rifampin—occurred in 2019, representing 3.3% and 18%, respectively, of all new and previously treated cases. Only 44% of these cases were diagnosed because of a lack of culture and drug susceptibility testing (DST) capacity in many settings worldwide. As a consequence, an estimated 200,000 people with MDR/RR-TB died in 2019. The countries of the former Soviet Union reported the highest proportions of MDR/RR disease among new TB cases (37% in Belarus, 35% in Russia, 29% in Kyrgyzstan, Moldova, and Ukraine). Overall, half of all MDR/RR-TB cases occur in India (27%), China (14%), and the Russian Federation (9%). Since 2006, 131 countries, including the United States, have reported cases of extensively drug-resistant TB (XDR-TB), in which MDR-TB is compounded by additional resistance to any fluoroquinolones and at least one of the injectable drugs amikacin, kanamycin, and capreomycin. (N.B: In January 2021, the 1360 TABLE 178-1 Risk Factors for Active Tuberculosis in Persons Who Have Been Infected with Tubercle Bacilli FACTOR Recent infection (<1 year) Fibrotic lesions (spontaneously healed) Comorbidities and iatrogenic causes HIV infection Silicosis Chronic renal failure/hemodialysis Diabetes IV drug use Excessive alcohol use Immunosuppressive treatment Tumor necrosis factor α inhibitors Gastrectomy Jejunoileal bypass Posttransplantation period (renal, cardiac) Tobacco smoking Malnutrition and severe underweight RELATIVE RISK/ODDSa 12.9 2–20 21–>30 30 10–25 2–4 10–30 3 10 4–5 2–5 30–60 20–70 2–3 2 Old infection = 1. a PART 5 Infectious Diseases with high-level transmissibility. When infection is acquired later in life, the chance is greater that the mature immune system will contain it at least temporarily. Bacilli, however, may persist for years before reactivating to produce secondary (or postprimary) TB, which, because of frequent cavitation, is more often infectious than is primary disease. Overall, it is estimated that up to 10% of infected persons will eventually develop active TB in their lifetime—half of them during the first 18 months after infection. The risk is much higher among immunocompromised individuals and, particularly, HIV-infected persons. Reinfection of a previously infected individual, which is common in areas with high rates of TB transmission, may also favor the development of disease. At the height of the TB resurgence in the United States in the early 1990s, molecular typing and comparison of strains of M. tuberculosis suggested that up to one-third of cases of active TB in some inner-city communities were due to recent transmission rather than to reactivation of old infection. Age is an important determinant of the risk of disease after infection. Among infected persons, the incidence of TB is highest during late adolescence and early adulthood; the reasons are unclear. The incidence among women peaks at 25–34 years of age. In this age group, rates among women may be higher than those among men, whereas at older ages the opposite is true. The risk increases in the elderly, possibly because of waning immunity and comorbidity. A variety of diseases and conditions favor the development of active TB (Table 178-1). In absolute terms, the most potent risk factor for TB among infected individuals is clearly HIV co-infection, which suppresses cellular immunity. The risk that infection will proceed to active disease is directly related to the patient’s degree of immunosuppression. In a study of HIV-co-infected, tuberculin skin test (TST)–positive persons, this risk varied from 2.6 to 13.3 cases/100 person-years and increased as the CD4+ T-cell count decreased. ■ NATURAL HISTORY OF DISEASE Studies conducted in various countries before the advent of antimicrobial TB therapy showed that untreated TB is often fatal. About one-third of patients died within 1 year after diagnosis. Historical data also show that 55% of sputum smear-positive cases were dead within 5 years and up to 86% (weighted mean 70%) within 10 years. A lower case fatality rate, around 20%, was estimated for untreated paucibacillary smear-negative cases at 5 years. Of the survivors at 5 years, ~60% had undergone spontaneous remission, while the remainder were still excreting tubercle bacilli. With effective, timely, and proper antimicrobial TB treatment, patients have a very high chance of being cured. However, improper use of anti-TB drugs, while reducing mortality rates, may also result in large numbers of chronic infectious cases, often with drug-resistant bacilli. PATHOGENESIS AND IMMUNITY ■ INFECTION AND MACROPHAGE INVASION The interaction of M. tuberculosis with the human host begins when droplet nuclei containing viable microorganisms, propelled into the air by infectious patients, are inhaled by a close bystander. Although the majority of inhaled bacilli are trapped in the upper airways and expelled by ciliated mucosal cells, a fraction (usually <10%) reach the alveoli, a unique immunoregulatory environment. There, in the very early phases of infection, the predominant cells infected by M. tuberculosis are myeloid dendritic cells. Subsequently, alveolar macrophages that have not yet been activated (prototypic alternatively activated macrophages) phagocytose the bacilli. Adhesion of mycobacteria to macrophages results largely from binding of the bacterial cell wall to a variety of macrophage cell-surface receptor molecules, including complement receptors, the mannose receptor, the immunoglobulin G Fcγ receptor, and type A scavenger receptors. Surfactants may also play a role in the early phase of interaction between the host and the pathogen, and surfactant protein D can prevent phagocytosis. Phagocytosis is enhanced by complement activation leading to opsonization of bacilli with C3 activation products such as C3b and C3bi. Concomitantly, binding of certain receptors, such as the mannose receptor, regulates postphagocytic events like phagosome–lysosome fusion and inflammatory cytokine production. After a phagosome forms, the survival of M. tuberculosis in the cell seems to depend in part on reduced acidification due to lack of assembly of a complete vesicular protonadenosine triphosphatase. A complex series of events is generated by the bacterial cell-wall lipoglycan lipoarabinomannan, which inhibits the intracellular increase of Ca2+. Thus, the Ca2+/calmodulin pathway (leading to phagosome–lysosome fusion) is impaired, and the bacilli survive within the phagosomes by blocking fusion. The M. tuberculosis phagosome inhibits the production of phosphatidylinositol 3-phosphate, which normally earmarks phagosomes for membrane sorting and maturation (including phagolysosome formation), which would destroy the bacteria. Bacterial factors block the host defense of autophagy, in which the cell sequesters the phagosome in a double-membrane vesicle (autophagosome) that is destined to fuse with lysosomes. If the bacilli are successful in arresting phagosome maturation, then replication begins and the macrophage eventually ruptures and releases its bacillary contents. This process is mediated by the ESX-1 secretion system that is encoded by genes contained in the region of difference 1 (RD1). Other uninfected phagocytic cells are then recruited to continue the infection cycle by ingesting dying macrophages and their bacillary content, thus, in turn, becoming infected themselves and expanding the infection. ■ VIRULENCE OF TUBERCLE BACILLI M. tuberculosis must be viewed as a complex formed by a multitude of strains that differ in virulence and are capable of producing a variety of manifestations of disease. Since the elucidation of the M. tuberculosis genome in 1998, large mutant collections have been generated, and many bacterial genes that contribute to M. tuberculosis virulence have been found. Moreover, different patterns of virulence defects have been defined in various animal models—predominantly mice but also guinea pigs, rabbits, and nonhuman primates. The katG gene encodes for a catalase/peroxidase enzyme that protects against oxidative stress and is required for isoniazid activation and subsequent bactericidal activity. RD1 is a 9.5-kb locus that encodes two key small protein antigens—6-kDa early secretory antigen (ESAT-6) and culture filtrate protein-10 (CFP-10)—as well as a putative secretion apparatus that may facilitate their egress; the absence of this locus in the vaccine strain M. bovis bacille Calmette-Guérin (BCG) is a key attenuating mutation. In M. marinum, a mutation in the RD1 virulence locus encoding the ESX-1 secretion system impairs the capacity of apoptotic macrophages to recruit uninfected cells for further rounds of infection. The results are less replication and fewer new granulomas. These observations in M. marinum are similar in part to events related to the virulence of M. tuberculosis; however, ESX-1, although necessary, is probably insufficient to explain virulence, and other mechanisms may be in play. Mutants lacking key enzymes of bacterial biosynthesis become auxotrophic for the missing substrate and often are totally unable to proliferate in animals; these include the leuCD and panCD mutants, which require leucine and pantothenic acid, respectively. The isocitrate lyase gene (icl1) encodes a key step in the glyoxylate shunt that facilitates bacterial growth on fatty acid substrates; this gene is required for long-term persistence of M. tuberculosis infection in mice with chronic TB. M. tuberculosis mutants in regulatory genes such as sigma factor C and sigma factor H (sigC and sigH) are associated with normal bacterial growth in mice, but they fail to elicit full tissue pathology. Finally, the mycobacterial protein CarD (expressed by the carD gene) seems essential for the control of rRNA transcription that is required for mycobacterial replication and persistence in the host cell. Its loss exposes mycobacteria to oxidative stress, starvation, DNA damage, and ultimately sensitivity to killing by a variety of host mutagens and defense mechanisms. ■ THE HOST RESPONSE, GRANULOMA FORMATION, AND “LATENCY” In the initial stage of host–bacterium interaction, prior to the onset of an acquired cell-mediated immune (CMI) response, M. tuberculosis disseminates widely through the lymph vessels, spreading to other sites in the lungs and other organs, and undergoes a period of extensive growth within naïve inactivated macrophages; additional naïve macrophages are recruited to the early granuloma. How the bacillus accesses the parenchymal tissue still needs to be elucidated: it may directly infect epithelial cells or transmigrate through infected macrophages across the epithelium. Infected dendritic cells or monocytes then begin to transport bacilli to the lymphatic system. Studies suggest that M. tuberculosis uses specific virulence mechanisms to subvert host cellular signaling and to elicit an early regulated proinflammatory response that promotes granuloma expansion and bacterial growth during this key early phase. A study of M. marinum infection in zebrafish has delineated one molecular mechanism by which mycobacteria induce granuloma formation. The mycobacterial protein ESAT-6 induces secretion of matrix metalloproteinase 9 (MMP9) by nearby epithelial cells that are in contact with infected macrophages. MMP9 in turn stimulates recruitment of naïve macrophages, thus inducing granuloma maturation and bacterial growth. Disruption of MMP9 function results in reduced bacterial growth. Another study has shown that M. tuberculosis–derived cyclic AMP is secreted from the phagosome into host macrophages, subverting the cell’s signal transduction pathways and stimulating an elevation in the secretion of tumor necrosis factor α (TNF-α) as well as further proinflammatory cell recruitment. Ultimately, the chemoattractants and bacterial products released during the repeated rounds of cell lysis and infection of newly arriving macrophages enable dendritic cells to access bacilli; these cells migrate to the draining lymph nodes and present mycobacterial antigens to T lymphocytes. At this point, the development of cell-mediated and humoral immunity begins. These initial stages of infection are usually asymptomatic. ■ MACROPHAGE-ACTIVATING RESPONSE Cell-mediated immunity is critical at this early stage. In the majority of infected individuals, local macrophages are activated when bacillary antigens processed by macrophages stimulate T lymphocytes to release a variety of lymphokines. These activated macrophages aggregate around the lesion’s center and effectively neutralize tubercle bacilli without causing further tissue destruction. In the central part of the lesion, the necrotic material resembles soft cheese (caseous necrosis)—a phenomenon that may also be observed in other conditions, such as neoplasms. Even when healing takes place, viable bacilli may remain dormant within macrophages or in the necrotic material for many years. These “healed” lesions in the lung parenchyma and hilar lymph nodes may later undergo calcification. ■ DELAYED-TYPE HYPERSENSITIVITY In a minority of cases, the macrophage-activating response is weak, and mycobacterial growth can be inhibited only by intensified delayed hypersensitivity reactions, which lead to lung tissue destruction. The lesion tends to enlarge further, and the surrounding tissue is 1361 CHAPTER 178 Tuberculosis ■ INNATE RESISTANCE TO INFECTION Several observations suggest that genetic factors play a key role in innate resistance to infection with M. tuberculosis and the development of disease. The existence of this resistance, which is polygenic in nature, is suggested by the differing degrees of susceptibility to TB in different populations. This mechanism of elimination of the pathogen may be accompanied by negative results in the TST and interferon-γ (IFN-γ) release assays (IGRAs). In mice, a gene called Nramp1 (natural resistance–associated macrophage protein 1) plays a regulatory role in resistance/susceptibility to mycobacteria. The human homologue NRAMP1, which maps to chromosome 2q, may play a role in determining susceptibility to TB, as is suggested by a study among West Africans. Studies of mice identified a novel host resistance gene, ipr1, that is encoded within the sst1 locus; ipr1 encodes an IFN-inducible nuclear protein that interacts with other nuclear proteins in macrophages primed with IFNs or infected by M. tuberculosis. In addition, polymorphisms in multiple genes, such as those encoding for various major histocompatibility complex alleles, IFN-γ, T-cell growth factor β, interleukin (IL) 10, mannose-binding protein, IFN-γ receptor, Toll-like receptor 2, vitamin D receptor, and IL-1, have been associated with susceptibility to TB. About 2–4 weeks after infection, two host responses to M. tuberculosis develop: a macrophage-activating CMI response and a tissue-damaging response. The macrophage-activating response is a T-cell mediated phenomenon resulting in the activation of macrophages that are capable of killing and digesting tubercle bacilli. The tissue-damaging response is the result of a delayed-type hypersensitivity reaction to various bacillary antigens; it destroys inactivated macrophages that contain multiplying bacilli but also causes caseous necrosis of the involved tissues (see below). Although both of these responses can inhibit mycobacterial growth, it is the balance between the two that determines the forms of TB that will develop subsequently. With the development of specific immunity and the accumulation of large numbers of activated macrophages at the site of the primary lesion, granulomatous lesions (tubercles) are formed. These lesions consist of accumulations of lymphocytes and activated macrophages that evolve toward epithelioid and giant cell morphologies. Initially, the tissue-damaging response can limit mycobacterial growth within macrophages. As stated above, this response, mediated by various bacterial products, not only destroys macrophages but also produces early solid necrosis in the center of the tubercle. Although M. tuberculosis can survive, its growth is inhibited within this necrotic environment by low oxygen tension and low pH. At this point, some lesions may heal by fibrosis, with subsequent calcification, whereas inflammation and necrosis occur in other lesions. Some observations have challenged the traditional view that any encounter between mycobacteria and macrophages results in chronic infection. It is possible that an immune response capable of eradicating early infection may sometimes develop as a consequence, for instance, of disabling mutations in mycobacterial genomes rendering their replication ineffective. Individual granulomas that are formed during this phase of infection can vary in size and cell composition; some can contain the spread of mycobacteria, while others cannot. TB infection ensues as a result of this dynamic balance between the microorganism and the host. For many years, TB infection has been called “latent TB infection (LTBI).” This terminology was used to define a state of persistent immune response to stimulation by M. tuberculosis antigens with no evidence of clinically manifest, active TB. The qualification “latent” may offer some convenience of distinguishing infection from disease, albeit an inaccurate description of a process that encompasses bacterial generations that are not dormant. It has been speculated that latency may therefore be an inaccurate term because bacilli may remain active during this “latent” stage, forming biofilms in necrotic areas within which they temporarily hide. Thus some have proposed the term persister as more accurate to indicate the behavior of the bacilli in this phase. It is important to recognize that infection and disease represent not a binary state but rather a continuum along which infection will eventually move in the direction of full containment or disease. The ability to predict, through systemic biomarkers, which affected individuals will progress toward disease would be of immense value in devising prophylactic interventions at scale. 1362 progressively damaged. At the center of the lesion, the caseous material liquefies. Bronchial walls and blood vessels are invaded and destroyed, and cavities are formed. The liquefied caseous material, containing large amount of bacilli, is drained through bronchi. Within the cavity, tubercle bacilli multiply, spill into the airways, and are discharged into the environment through expiratory maneuvers such as coughing and talking. In the early stages of infection, bacilli are usually transported by macrophages to regional lymph nodes, from which they gain access to the central venous return; from there they reseed the lungs and may also disseminate beyond the pulmonary vasculature throughout the body via the systemic circulation. The resulting extrapulmonary lesions may undergo the same evolution as those in the lungs, although most tend to heal. In young children with poor natural immunity, hematogenous dissemination may result in fatal miliary TB or tuberculous meningitis. PART 5 Infectious Diseases ■ ROLE OF MACROPHAGES AND MONOCYTES While cell-mediated immunity confers partial protection against M. tuberculosis, humoral immunity plays a less well-defined role in protection (although evidence is accumulating on the existence of antibodies to lipoarabinomannan, which may prevent dissemination of infection in children). In cell-mediated immunity, two types of cells are essential: macrophages, which directly phagocytose tubercle bacilli, and T cells (mainly CD4+ T lymphocytes, although the role of CD8+ T cells has recently been the subject of much research), which induce protection through the production of cytokines, especially IFN-γ. After infection with M. tuberculosis, alveolar macrophages secrete various cytokines responsible for a number of events (e.g., the formation of granulomas) as well as systemic effects (e.g., fever and weight loss). However, alternatively activated alveolar macrophages may be particularly susceptible to M. tuberculosis growth early on, given their more limited proinflammatory and bactericidal activity, which is related in part to being bathed in surfactant. New monocytes and macrophages attracted to the site are key components of the immune response. Their primary mechanism is probably related to production of oxidants (such as reactive oxygen intermediates or nitric oxide) that have antimycobacterial activity and increase the synthesis of cytokines such as TNF-α and IL-1, which in turn regulate the release of reactive oxygen intermediates and reactive nitrogen intermediates. In addition, macrophages can undergo apoptosis—a defensive mechanism to prevent the release of cytokines and bacilli via their sequestration in the apoptotic cell. Recent work also describes the involvement of neutrophils in the host response, although the timing of their appearance and their effectiveness remain uncertain. ■ ROLE OF T LYMPHOCYTES Alveolar macrophages, monocytes, and dendritic cells are also critical in processing and presenting antigens to T lymphocytes, primarily CD4+ and CD8+ T cells; the result is the activation and proliferation of CD4+ T lymphocytes, which are crucial to the host’s defense against M. tuberculosis. Qualitative and quantitative defects of CD4+ T cells explain the inability of HIV-infected individuals to contain mycobacterial proliferation. Activated CD4+ T lymphocytes can differentiate into cytokine-producing TH1 or TH2 cells. TH1 cells produce IFN-γ—an activator of macrophages and monocytes—and IL-2. TH2 cells produce IL-4, IL-5, IL-10, and IL-13 and may also promote humoral immunity. The interplay of these various cytokines and their cross-regulation determine the host’s response. The role of cytokines in promoting intracellular killing of mycobacteria, however, has not been entirely elucidated. IFN-γ may induce the generation of reactive nitrogen intermediates and regulate genes involved in bactericidal effects. TNF-α is also important. Although its precise mechanisms are complex and not yet fully clarified, a model has been suggested that foresees an ideal setting for TNF-α between excessive activation—with consequent worsening of immunopathological reactions—and insufficient activation— with resulting lack of containment—in the control of TB infection. Observations made originally in transgenic knockout mice and more recently in humans suggest that other T-cell subsets, especially CD8+ T cells, may play an important role. CD8+ T cells have been associated with protective activities via cytotoxic responses and lysis of infected cells as well as with production of IFN-γ and TNF-α. Finally, natural killer cells act as co-regulators of CD8+ T-cell lytic activities, and γδ T cells are increasingly thought to be involved in protective responses in humans. ■ MYCOBACTERIAL LIPIDS AND PROTEINS Lipids are involved in mycobacterial recognition by the innate immune system, and lipoproteins (such as 19-kDa lipoprotein) trigger potent signals through Toll-like receptors present in blood dendritic cells. M. tuberculosis possesses various protein antigens. Some are present in the cytoplasm and cell wall; others are secreted. That the latter are more important in eliciting a T lymphocyte response is suggested by experiments documenting the appearance of protective immunity in animals after immunization with live, protein-secreting mycobacteria. Among the antigens that may play a protective role are the 30-kDa (or 85B) and ESAT-6 antigens. Protective immunity is probably the result of reactivity to many different mycobacterial antigens. These antigens are being incorporated into newly designed vaccines on various platforms. ■ SKIN-TEST REACTIVITY Coincident with the appearance of immunity, delayed-type hypersensitivity to M. tuberculosis develops. This reactivity is the basis of the TST, which is used primarily for the diagnosis of M. tuberculosis infection in persons without symptoms. The cellular mechanisms responsible for TST reactivity are related mainly to previously sensitized CD4+ T lymphocytes, which are attracted to the skin-test site. There, they proliferate and produce cytokines. Although delayed hypersensitivity is associated with protective immunity (TST-positive persons are less susceptible to a new M. tuberculosis infection than TST-negative persons), it by no means guarantees protection against reactivation. In fact, cases of active TB are often accompanied by strongly positive skintest reactions. There is also evidence of reinfection with a new strain of M. tuberculosis in patients previously treated for active disease. This evidence underscores the fact that previous infection or active TB may not confer fully protective immunity. CLINICAL MANIFESTATIONS TB is classified as pulmonary, extrapulmonary, or both. Depending on several factors linked to host immunological status and bacterial strains, extrapulmonary TB may occur in 10–40% of patients. Furthermore, up to two-thirds of HIV-infected patients with TB may have both pulmonary and extrapulmonary TB or extrapulmonary TB alone. ■ PULMONARY TB Pulmonary TB is conventionally categorized as primary or postprimary (adult-type, secondary). This distinction has been challenged by molecular evidence from TB-endemic areas indicating that a large percentage of cases of adult pulmonary TB result from recent infection (either primary infection or reinfection) and not from reactivation. Primary Disease Primary pulmonary TB occurs soon after the initial infection. It may be asymptomatic or may present with fever and occasionally pleuritic chest pain. In areas of high TB transmission, this form of disease is often seen in children. Because most inspired air is distributed to the middle and lower lung zones, these areas are most commonly involved in primary TB. The lesion forming after initial infection (Ghon focus) is usually peripheral and accompanied by transient hilar or paratracheal lymphadenopathy, which may or may not be visible on standard chest radiography (CXR) (Fig. 178-4). Some patients develop erythema nodosum on the legs (see Fig. A1-39) or phlyctenular conjunctivitis. In the majority of cases, the lesion heals spontaneously and becomes evident only as a small calcified nodule. Pleural reaction overlying a subpleural focus is also common. The Ghon focus, with or without overlying pleural reaction, thickening, and regional lymphadenopathy, is referred to as the Ghon complex. In young children with immature cell-mediated immunity and in persons with impaired immunity (e.g., those with malnutrition or HIV infection), primary pulmonary TB may progress rapidly to clinical illness. The initial lesion increases in size and can evolve in different ways. Pleural effusion, which is found in up to two-thirds of cases, 1363 FIGURE 178-4 Chest radiograph showing right hilar lymph node enlargement with infiltration into the surrounding lung tissue in a child with primary tuberculosis. (Courtesy of Prof. Robert Gie, Department of Paediatrics and Child Health, Stellenbosch University, South Africa; with permission.) FIGURE 178-5 Chest radiograph showing bilateral miliary (millet-sized) infiltrates in a child. (Courtesy of Prof. Robert Gie, Department of Paediatrics and Child Health, Stellenbosch University, South Africa; with permission.) and may cause locally progressive disease or result in tuberculous meningitis; this is a particular concern in very young children and immunocompromised persons (e.g., patients with HIV infection). Postprimary (Adult-Type) Disease Also referred to as reactivation or secondary TB, postprimary TB is probably most accurately termed adult-type TB because it may result from endogenous reactivation of distant or recent infection (primary infection or reinfection). It is usually localized to the apical and posterior segments of the upper lobes, where the substantially higher mean oxygen tension (compared with that in the lower zones) favors mycobacterial growth. The superior segments of the lower lobes are also frequently involved. The extent of lung parenchymal involvement varies greatly, from small infiltrates to extensive cavitary disease. With cavity formation, liquefied necrotic contents are ultimately discharged into the airways and may undergo bronchogenic spread, resulting in satellite lesions within the lungs that may in turn undergo cavitation (Figs. 178-6 and 178-7). Massive involvement of pulmonary segments or lobes, FIGURE 178-7 CT scan showing a large cavity in the right lung of a patient with active tuberculosis. (Courtesy of Dr. Elisa Busi Rizzi, National Institute for Infectious Diseases, Spallanzani Hospital, Rome, Italy; with permission.) CHAPTER 178 Tuberculosis results from the penetration of bacilli into the pleural space from an adjacent subpleural focus. In severe cases, the primary site rapidly enlarges, its central portion undergoes necrosis, and cavitation develops (progressive primary TB). TB in young children is almost invariably accompanied by hilar or paratracheal lymphadenopathy due to the spread of bacilli from the lung parenchyma through lymphatic vessels. Enlarged lymph nodes may compress bronchi, causing total obstruction with distal collapse, partial obstruction with large-airway wheezing, or a ball-valve effect with segmental/lobar hyperinflation. Lymph nodes may also rupture into the airway with development of pneumonia, often including areas of necrosis and cavitation, distal to the obstruction. Bronchiectasis (Chap. 290) may develop in any segment/ lobe damaged by progressive caseating pneumonia. Occult hematogenous dissemination commonly follows primary infection. However, in the absence of a sufficient acquired immune response, which usually contains the infection, disseminated or miliary disease may result (Fig. 178-5). Small granulomatous lesions develop in multiple organs FIGURE 178-6 Chest radiograph showing a right-upper-lobe infiltrate and a cavity with an air-fluid level in a patient with active tuberculosis. (Courtesy of Dr. Andrea Gori, Infectious Diseases Unit, Fondazione IRCCS Ca’ Granda Ospediale Maggiore Policlinico, University of Milan, Milan, Italy; with permission.) 1364 PART 5 Infectious Diseases with coalescence of lesions, produces caseating pneumonia. While up to one-third of untreated patients reportedly succumb to severe pulmonary TB within a few months after onset (the classic “galloping consumption” of the past), others may undergo a process of spontaneous remission or proceed along a chronic, progressively debilitating course (“consumption” or phthisis). Under these circumstances, some pulmonary lesions become fibrotic and may later calcify, but cavities persist in other parts of the lungs. Individuals with such chronic disease continue to discharge tubercle bacilli into the environment. Most patients respond to treatment, with defervescence, decreasing cough, weight gain, and a general improvement in well-being within several weeks. Early in the course of disease, symptoms and signs are often nonspecific and insidious, consisting mainly of fever, often diurnal and night sweats due to defervescence, weight loss, anorexia, general malaise, and weakness. However, in up to 90% of cases, cough eventually develops—often initially nonproductive and limited to the morning and subsequently accompanied by the production of purulent sputum, sometimes with blood streaking. Hemoptysis develops in 20–30% of cases, and massive hemoptysis may ensue as a consequence of the erosion of a blood vessel in the wall of a cavity. Hemoptysis, however, may also result from rupture of a dilated vessel in a cavity (Rasmussen’s aneurysm) or from aspergilloma formation in an old cavity. Pleuritic chest pain sometimes develops in patients with subpleural parenchymal lesions or pleural disease. Extensive disease may produce dyspnea and, in rare instances, adult respiratory distress syndrome. Physical findings are of limited use in pulmonary TB. Many patients have no abnormalities detectable by chest examination, whereas others have detectable rales in the involved areas during inspiration, especially after coughing. Occasionally, rhonchi due to partial bronchial obstruction and classic amphoric breath sounds in areas with large cavities may be heard. Systemic features include fever (often low-grade and intermittent) in up to 80% of cases and wasting. Absence of fever, however, does not exclude TB. In some recurrent cases and among people with low Karnofsky score, finger clubbing has been reported. The most common hematologic findings are mild anemia, leukocytosis, and thrombocytosis with a slightly elevated erythrocyte sedimentation rate and/or C-reactive protein level. None of these findings is consistent or sufficiently accurate for diagnostic purposes. Hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone has also been reported. ■ EXTRAPULMONARY TB In descending order of frequency, the extrapulmonary sites most commonly involved in TB are the lymph nodes, pleura, genitourinary tract, bones and joints, meninges, peritoneum, and pericardium. However, virtually any organ system may be affected. As a result of hematogenous dissemination in HIV-infected individuals, extrapulmonary TB is seen more commonly today than in the past in settings of high HIV prevalence. Lymph Node TB (Tuberculous Lymphadenitis) The most common presentation of extrapulmonary TB in both HIV-seronegative individuals and HIV-infected patients (35% of cases worldwide and >40% of cases in the United States in recent series), lymph node disease is particularly frequent among HIV-infected patients and among children (Fig. 178-8). In the United States, besides children, women (particularly non-Caucasians) seem to be especially susceptible. Once caused mainly by M. bovis, tuberculous lymphadenitis today is due largely to M. tuberculosis. Lymph node TB presents as painless swelling of the lymph nodes, most commonly at posterior cervical and supraclavicular sites (a condition historically referred to as scrofula). Lymph nodes are usually discrete in early disease but develop into a matted nontender mass over time; a fistulous tract draining caseous material may result. Associated pulmonary disease is present in fewer than 50% of cases, and systemic symptoms are uncommon except in HIV-infected patients. The diagnosis is established by fine-needle aspiration biopsy (with a yield of up to 80%) or surgical excision biopsy. Bacteriologic confirmation is achieved in the vast majority of cases, FIGURE 178-8 Tuberculous lymphadenitis affecting the cervical lymph nodes in a 2-year-old child from Malawi. (Courtesy of Prof. S. Graham, Centre for International Child Health, University of Melbourne, Australia; with permission.) granulomatous lesions with or without visible AFBs are typically seen, and cultures are positive in 70–80% of cases. Among HIV-infected patients, granulomas are less well organized and are frequently absent entirely, but bacterial loads are heavier than in HIV-seronegative patients, with higher yields from microscopy and culture. Differential diagnosis includes a variety of infectious conditions, neoplastic diseases such as lymphomas or metastatic carcinomas, and rare disorders like Kikuchi’s disease (necrotizing histiocytic lymphadenitis), Kimura’s disease, and Castleman’s disease. Pleural TB Involvement of the pleura accounts for ~20% of extrapulmonary cases in the United States and elsewhere. Isolated pleural effusion usually reflects recent primary infection, and the collection of fluid in the pleural space represents a hypersensitivity response to mycobacterial antigens. Pleural disease may also result from contiguous parenchymal spread, as in many cases of pleurisy accompanying postprimary disease. Depending on the extent of reactivity, the effusion may be small, remain unnoticed, and resolve spontaneously or may be sufficiently large to cause symptoms such as fever, pleuritic chest pain, and dyspnea. Physical findings are those of pleural effusion: dullness to percussion and absence of breath sounds. CXR reveals the effusion and, in up to one-third of cases, also shows a parenchymal lesion. Thoracentesis is required to ascertain the nature of the effusion and to differentiate it from manifestations of other etiologies. The fluid is straw-colored and at times hemorrhagic; it is an exudate with a protein concentration >50% of that in serum (usually ~4–6 g/dL), a normal to low glucose concentration, a pH of ~7.3 (occasionally <7.2), and detectable white blood cells (usually 500–6000/μL). Neutrophils may predominate in the early stage, but lymphocyte predominance is the typical finding later. Mesothelial cells are generally rare or absent. AFBs are rarely seen on direct smear, and cultures often may be falsely negative for M. tuberculosis; positive cultures are more common among postprimary cases. Determination of the pleural concentration of adenosine deaminase may be a useful screening test, and TB may be excluded if the value is very low. Lysozyme is also present in the pleural effusion. Measurement of IFN-γ, either directly or through stimulation of sensitized T cells with mycobacterial antigens, can be diagnostically helpful. Needle biopsy of the pleura is often required for diagnosis and is recommended over pleural fluid analysis; it reveals granulomas and/or yields a positive culture in up to 80% of cases. Pleural biopsy can yield a positive result in ~75% of cases when real-time automated nucleic acid amplification is used (the Xpert MTB/RIF assay [Cepheid; Sunnyvale, CA]; see “Nucleic Acid Amplification Technology,” below); testing of pleural fluid with this assay is not recommended because of low sensitivity. This form of pleural TB responds rapidly to chemotherapy and may resolve spontaneously. Concurrent glucocorticoid administration may reduce the duration of fever and/or chest pain but is not of proven benefit. Tuberculous empyema is a less common complication of pulmonary TB. It is usually the result of the rupture of a cavity, with spillage of a large number of organisms into the pleural space. This process may create a bronchopleural fistula with evident air in the pleural space. CXR shows hydropneumothorax with an air-fluid level. The pleural fluid is purulent and thick and contains large numbers of lymphocytes. Acid-fast smears and mycobacterial cultures are often positive. Surgical drainage is usually required as an adjunct to chemotherapy. Tuberculous empyema may result in severe pleural fibrosis and restrictive lung disease. Removal of the thickened visceral pleura (decortication) is occasionally necessary to improve lung function. 1365 TB of the Upper Airways Nearly always a complication of advanced cavitary pulmonary TB, TB of the upper airways may involve the larynx, pharynx, and epiglottis. Symptoms include hoarseness, dysphonia, and dysphagia in addition to chronic productive cough. Findings depend on the site of involvement, and ulcerations may be seen on laryngoscopy. Acid-fast smear of the sputum is often positive, but biopsy may be necessary in some cases to establish the diagnosis. Carcinoma of the larynx may have similar features but is usually painless. Genitourinary TB Genitourinary TB, which accounts for ~10– FIGURE 178-9 MRI of culture-confirmed renal tuberculosis. T2-weighted coronary plane: coronal sections showing several renal lesions in both the cortical and the medullary tissues of the right kidney. (Courtesy of Dr. Alberto Matteelli, Department of Infectious Diseases, University of Brescia, Italy; with permission.) in female than in male patients. In female patients, it affects the fallopian tubes and the endometrium and may cause infertility, pelvic pain, and menstrual abnormalities. Diagnosis requires biopsy or culture of specimens obtained by dilation and curettage. In male patients, genital TB preferentially affects the epididymis, producing a slightly tender mass that may drain externally through a fistulous tract; orchitis and prostatitis may also develop. In almost half of cases of genitourinary TB, urinary tract disease is also present. Genitourinary TB responds well to chemotherapy. Skeletal TB In the United States, TB of the bones and joints is responsible for ~10% of extrapulmonary cases. In bone and joint disease, pathogenesis is related to reactivation of hematogenous foci or to spread from adjacent paravertebral lymph nodes. Weight-bearing joints (the spine in 40% of cases, the hips in 13%, and the knees in 10%) are most commonly affected. Spinal TB (Pott’s disease or tuberculous spondylitis; Fig. 178-10) often involves two or more adjacent vertebral bodies. Whereas the upper thoracic spine is the most common site of spinal TB in children, the lower thoracic and upper lumbar vertebrae are usually affected in adults. From the anterior superior or inferior angle of the vertebral body, the lesion slowly reaches the adjacent body, later affecting the intervertebral disk. With advanced disease, collapse of vertebral bodies results in kyphosis (gibbus). A paravertebral “cold” abscess may also form. In the upper spine, this abscess may track to and penetrate the chest wall, presenting as a soft tissue mass; in the lower spine, it may reach the inguinal ligaments or present as a psoas abscess. CT or MRI reveals the characteristic lesion and suggests its etiology. The differential diagnosis includes tumors and other infections. Pyogenic bacterial osteomyelitis, in particular, involves the disk very early and produces rapid sclerosis. Aspiration of the abscess or bone biopsy confirms the tuberculous etiology, as cultures are usually positive and histologic findings highly typical. A catastrophic complication of Pott’s disease is paraplegia, which is usually due to an abscess or a lesion compressing the spinal cord. Paraparesis due to a large abscess is a medical emergency and requires rapid drainage. TB of the hip joints, usually involving the head of the femur, causes pain; TB of the knee produces pain and swelling. If the disease goes unrecognized, the joints may be destroyed. Diagnosis requires examination of the synovial fluid, which is thick in appearance, with a high protein concentration and a variable cell count. Although synovial fluid culture is positive in a high percentage of cases, synovial biopsy and tissue culture may be necessary to establish the diagnosis. Skeletal TB responds to chemotherapy, but severe cases may require surgery. Tuberculous Meningitis and Tuberculoma TB of the central nervous system (CNS) accounts for ~5% of extrapulmonary cases in CHAPTER 178 Tuberculosis 15% of all extrapulmonary cases in the United States and elsewhere, may involve any portion of the genitourinary tract. Clinical manifestations are cryptic and protean. Patients may be asymptomatic and their disease discovered only after destructive lesions of the kidneys have developed. Symptoms are often nonspecific, and include those of urinary tract infection with frequency, dysuria, nocturia and hematuria, and abdominal or flank pain. Without a high index of suspicion, this form of TB m