Etiology

There are 5 closely related mycobacteria in the M. tuberculosis complex: M. tuberculosis, M. bovis, M. africanum, M. microti, and M. canetti. M. tuberculosis is the most important cause of tuberculosis disease in humans. The tubercle bacilli are non–spore-forming, nonmotile, pleomorphic, weakly gram-positive curved rods 2-4 µm long. They can appear beaded or clumped in stained clinical specimens or culture media. They are obligate aerobes that grow in synthetic media containing glycerol as the carbon source and ammonium salts as the nitrogen source (Loewenstein-Jensen culture media). These mycobacteria grow best at 37-41°C, produce niacin, and lack pigmentation. A lipid-rich cell wall accounts for resistance to the bactericidal actions of antibody and complement. A hallmark of all mycobacteria is acid fastness—the capacity to form stable mycolate complexes with arylmethane dyes such as crystal violet, carbolfuchsin, auramine, and rhodamine. Once stained, they resist decoloration with ethanol and hydrochloric or other acids.

Mycobacteria grow slowly, with a generation time of 12-24 hr. Isolation from clinical specimens on solid synthetic media usually takes 3-6 wk, and drug susceptibility testing requires an additional 4 wk. Growth can be detected in 1-3 wk in selective liquid medium using radiolabeled nutrients (e.g., the BACTEC radiometric system), and drug susceptibilities can be determined in an additional 3-5 days. Once mycobacterial growth is detected, the species of mycobacteria present can be determined within hours using high-pressure liquid chromatography analysis (based on the fact that each species has a unique fingerprint of mycolic acids) or DNA probes. The presence of M. tuberculosis in clinical specimens sometimes can be detected directly within hours using nucleic acid amplification (NAA) tests (including polymerase chain reaction) that employ a DNA probe complementary to mycobacterial DNA or RNA. Data from children are limited, but the sensitivity of some NAA techniques is similar to that for culture for pulmonary tuberculosis and is better than culture for extrapulmonary disease. Restriction fragment length polymorphism (RFLP) profiling of mycobacteria is a helpful tool to study the epidemiology of tuberculosis.

Epidemiology

Latent tuberculosis infection (LTBI) occurs after the inhalation of infective droplet nuclei containing M. tuberculosis. A reactive tuberculin skin test (TST) and the absence of clinical and radiographic manifestations are the hallmark of this stage. The word tuberculosis refers to disease that occurs when signs and symptoms or radiographic changes become apparent. Untreated infants with LTBI have up to a 40% likelihood of developing tuberculosis, with the risk for progression decreasing gradually through childhood to adult lifetime rates of 5-10%. The greatest risk for progression occurs in the first 2 yr after infection.

The World Health Organization estimates that 30% of the world’s population (2 billion people) are infected with M. tuberculosis. Infection rates are highest in Africa, Asia, and Latin America (see Fig. 207-2). The global burden of tuberculosis continues to grow owing to several factors, including the impact of HIV epidemics, population migration patterns, increasing poverty, social upheaval and crowded living conditions in developing countries and in inner city populations in developed countries, inadequate health coverage and poor access to health services, and inefficient tuberculosis control programs.

Tuberculosis case rates decreased steadily in the USA during the 1st half of the 20th century, long before the advent of antituberculosis drugs, as a result of improved living conditions and, likely, genetic selection favoring persons resistant to developing disease. A resurgence of tuberculosis in the late 1980s was associated primarily with the HIV epidemic and transmission of the organism in congregate settings, adding to increased immigration and poor tuberculosis control (see Fig. 207-3). Since 1992, the number of reported cases of tuberculosis has decreased each year, reaching a record low of 12,904 cases (rate of 4.2/100,000 population) in the year 2008. Of these, 786 (6.1%) cases occurred in children <15 yr of age (rate 1.3/100,000 population). The decline in overall incidence was mostly due to a substantial decrease in cases in persons born in the USA. About 59% of all cases were among foreign-born persons. The total number of cases among foreign-born persons increased 5% between 1992 and 2005 (see Fig. 207-4). In all age groups, the proportion of reported cases was strikingly higher in foreign-born and nonwhite persons, even though the number of cases among foreign-born children <15 yr of age has declined. In white populations in the USA, tuberculosis rates are highest among the elderly who acquired the infection decades ago. In contrast, among nonwhite populations, tuberculosis is most common in young adults and children <5 yr of age. The age range of 5-14 yr is often called the “favored age,” because in all human populations this group has the lowest rate of tuberculosis disease. Among adults two thirds of cases occur in men, but in children there is no significant difference in sex distribution.

In the USA, most children are infected with M. tuberculosis in their home by someone close to them, but outbreaks of childhood tuberculosis also occur in elementary and high schools, nursery schools, daycare centers and homes, churches, school buses, and sports teams. HIV-infected adults with tuberculosis can transmit M. tuberculosis to children, and children with HIV infection are at increased risk for developing tuberculosis after infection. Specific groups are at high risk for acquiring tuberculosis infection and progressing from LTBI to tuberculosis (Table 207-1).

The incidence of drug-resistant tuberculosis has increased dramatically throughout the world. In the USA, about 8% of M. tuberculosis isolates are resistant to at least isoniazid, whereas 1% are resistant to both isoniazid and rifampin. Resistance to isoniazid remained relatively stable between 1992 and 2008, as did the proportion of cases that were multidrug resistant (about 1%). In some countries, drug resistance rates range from 20% to 50%. The major reasons for the development of drug resistance are the patient’s poor adherence to treatment and provision of inadequate drug regimens by the physician or national tuberculosis program.

Transmission

Transmission of M. tuberculosis is person to person, usually by airborne mucus droplet nuclei, particles 1-5 µm in diameter that contain M. tuberculosis. Transmission rarely occurs by direct contact with an infected discharge or a contaminated fomite. The chance of transmission increases when the patient has a positive acid-fast smear of sputum, an extensive upper lobe infiltrate or cavity, copious production of thin sputum, and severe and forceful cough. Environmental factors such as poor air circulation enhance transmission. Most adults no longer transmit the organism within several days to 2 weeks after beginning adequate chemotherapy, but some patients remain infectious for many weeks. Young children with tuberculosis rarely infect other children or adults. Tubercle bacilli are sparse in the endobronchial secretions of children with pulmonary tuberculosis, and cough is often absent or lacks the tussive force required to suspend infectious particles of the correct size. Children and adolescents with adult-type cavitary or endobronchial pulmonary tuberculosis can transmit the organism. Airborne transmission of M. bovis and M. africanum can also occur. M. bovis can penetrate the gastrointestinal (GI) mucosa or invade the lymphatic tissue of the oropharynx when large numbers of the organism are ingested. Human infection with M. bovis is rare in developed countries as a result of the pasteurization of milk and effective tuberculosis-control programs for cattle. About 30% of culture-proven childhood tuberculosis cases in San Diego, California, since 1990 were caused by M. bovis, likely acquired by children when visiting Mexico or another country with suboptimal veterinary tuberculosis-control programs.

Pathogenesis

The primary complex of tuberculosis includes local infection at the portal of entry and the regional lymph nodes that drain the area (Fig. 207-5). The lung is the portal of entry in >98% of cases. The tubercle bacilli multiply initially within alveoli and alveolar ducts. Most of the bacilli are killed, but some survive within nonactivated macrophages, which carry them through lymphatic vessels to the regional lymph nodes. When the primary infection is in the lung, the hilar lymph nodes usually are involved, although an upper lobe focus can drain into paratracheal nodes. The tissue reaction in the lung parenchyma and lymph nodes intensifies over the next 2-12 wk as the organisms grow in number and tissue hypersensitivity develops. The parenchymal portion of the primary complex often heals completely by fibrosis or calcification after undergoing caseous necrosis and encapsulation (Fig. 207-6). Occasionally, this portion continues to enlarge, resulting in focal pneumonitis and pleuritis. If caseation is intense, the center of the lesion liquefies and empties into the associated bronchus, leaving a residual cavity.

Figure 207-5 Overview of the immune response in tuberculosis. Control of Mycobacterium tuberculosis is mainly the result of productive teamwork between T-cell populations and macrophages (Mφ). M. tuberculosis survives within macrophages and dendritic cells (DCs) inside the phagosomal compartment. Gene products of MHC class II are loaded with mycobacterial peptides that are presented to CD4 T cells. CD8 T-cell stimulation requires loading of MHC I molecules by mycobacterial peptides in the cytosol, either by egression of mycobacterial antigens into the cytosol or cross-priming, by which macrophages release apoptotic bodies carrying mycobacterial peptides. These vesicles are taken up by DCs and peptides presented. The CD4 T-helper (Th) cells polarize into different subsets. DCs and macrophages express pattern recognition receptors (PRRs), which sense molecular patterns on pathogens. Th1 cells produce IL-2 for T-cell activation, interferon-γ (IFN-γ), or tumor necrosis factor (TNF) for macrophage activation. Th17 cells, which activate polymorphonuclear granulocytes (PNGs), contribute to the early formation of protective immunity in the lung after vaccination. Th2 cells and regulatory T cells (Treg) counter-regulate Th1-mediated protection via IL4, transforming growth factor β (TGF-β), or IL10. CD8 T cells produce IFN-γ and TNF, which activate macrophages. They also act as cytolytic T lymphocytes (CTL) by secreting perforin and granulysin, which lyse host cells and directly attack M. tuberculosis. These effector T cells (T_eff) are succeeded by memory T cells T_M). T_M cells produce multiple cytokines, notably IL2, IFN-γ, and TNF. During active containment in solid granuloma, M. tuberculosis recesses into a dormant stage and is immune to attack. Exhaustion of T cells is mediated by interactions between T cells and DCs through members of the programmed death 1 system. Treg cells secrete IL10 and TGF-β, which suppress Th1. This process allows resuscitation of M. tuberculosis, which leads to granuloma caseation and active disease. B, B cell.

(From Kaufman SHE, Hussey G, Lambert PH: New vaccines for tuberculosis. Lancet 375:2110–2118, 2010.)

Figure 207-6 A and B, Posteroanterior and lateral chest radiograph images of an adolescent showing a 7-mm calcified granuloma in the left lower lobe (arrows).

(From Lighter J, Rigaud M: Diagnosing childhood tuberculosis: traditional and innovative modalities, Curr Prob Pediatr Adolesc Health Care 39:55–88, 2009.)

The foci of infection in the regional lymph nodes develop some fibrosis and encapsulation, but healing is usually less complete than in the parenchymal lesion. Viable M. tuberculosis can persist for decades within these foci. In most cases of initial tuberculosis infection, the lymph nodes remain normal in size. However, hilar and paratracheal lymph nodes that enlarge significantly as part of the host inflammatory reaction can encroach on a regional bronchus (Figs. 207-7 and 207-8). Partial obstruction of the bronchus caused by external compression can cause hyperinflation in the distal lung segment. Complete obstruction results in atelectasis. Inflamed caseous nodes can attach to the bronchial wall and erode through it, causing endobronchial tuberculosis or a fistula tract. The caseum causes complete obstruction of the bronchus. The resulting lesion is a combination of pneumonitis and atelectasis and has been called a collapse-consolidation or segmental lesion (Fig. 207-9).

Figure 207-7 A 14 yr old child with proven primary tuberculosis. Frontal (A) and lateral (B) views of the chest show hyperinflation, prominent left hilar lymphadenopathy, and alveolar consolidation involving the posterior segment of the left upper love as well as the superior segment of the left lower lobe.

(From Hilton SVW, Edwards DK, editors: Practical pediatric radiology, ed 3, Philadelphia, 2003, Saunders, p 334.)

Figure 207-8 An 8 yr old child with a history of cough. A single frontal view of the chest shows marked right hilar and paratracheal lymphadenopathy with alveolar disease involving the right middle and lower lung fields. This was also a case of primary tuberculosis.

(From Hilton SVW, Edwards DK, editors: Practical pediatric radiology, ed 3, Philadelphia, 2003, Saunders, p 335.)

Figure 207-9 Right-sided hilar lymphadenopathy and collapse-consolidation lesions of primary tuberculosis in a 4 yr old child.

During the development of the primary complex (Ghon complex), which is the combination of a parenchymal pulmonary lesion and a corresponding lymph node site, tubercle bacilli are often carried to most tissues of the body through the blood and lymphatic vessels. Although seeding of the organs of the reticuloendothelial system is common, bacterial replication is more likely to occur in organs with conditions that favor their growth, such as the lung apices, brain, kidneys, and bones. Disseminated tuberculosis occurs if the number of circulating bacilli is large and the host’s cellular immune response is inadequate. More often the number of bacilli is small, leading to clinically inapparent metastatic foci in many organs. These remote foci usually become encapsulated, but they may be the origin of both extrapulmonary tuberculosis and reactivation tuberculosis in some persons.

The time between initial infection and clinically apparent disease is variable. Disseminated and meningeal tuberculosis are early manifestations, often occurring within 2-6 mo of acquisition. Significant lymph node or endobronchial tuberculosis usually appears within 3-9 mo. Lesions of the bones and joints take several years to develop, whereas renal lesions become evident decades after infection. Extrapulmonary manifestations develop in 25-35% of children with tuberculosis, compared with about 10% of immunocompetent adults with tuberculosis.

Pulmonary tuberculosis that occurs >1 yr after the primary infection is usually caused by endogenous regrowth of bacilli persisting in partially encapsulated lesions. This reactivation tuberculosis is rare in children but is common among adolescents and young adults. The most common form is an infiltrate or cavity in the apex of the upper lobes, where oxygen tension and blood flow are great.

The risk for dissemination of M. tuberculosis is very high in HIV-infected persons. Reinfection also can occur in persons with advanced HIV or AIDS. In immunocompetent persons the response to the initial infection with M. tuberculosis usually provides protection against reinfection when a new exposure occurs. However, exogenous reinfection has been reported to occur in adults without immune compromise in highly endemic areas.