Henry M. Blumberg MD, FACP1
Professor of Medicine
Michael K. Leonard Jr MD2
Assistant Professor of Medicine
1Emory University School of Medicine
2Division of Infectious Diseases, Emory University School of Medicine
The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Tuberculosis is a bacterial disease caused by Mycobacterium tuberculosis, a relatively slow-growing, aerobic, acid-fast bacillus. Classically, tuberculosis is a pulmonary disease, but disseminated and extrapulmonary manifestations may also occur, especially in immunocompromised persons. Tuberculosis is transmitted person to person and is usually contracted by inhalation of M. tuberculosis droplet nuclei generated by an infectious person.
If infection occurs after M. tuberculosis enters the body, the host's cell-mediated immunity may contain the organism but not eradicate all the bacilli, resulting in latent tuberculosis infection (LTBI). M. tuberculosis can remain dormant and persist (e.g., within macrophages); persons with LTBI are at risk for reactivation and development of active tuberculosis. Treatment of LTBI can markedly reduce the risk of progression to active disease.1,2
If host defenses are unable to contain the infection, the bacillary load increases markedly and LTBI progresses to active tuberculosis. Persons with tuberculosis (also called tuberculosis disease or active tuberculosis) generally are symptomatic and may be infectious if they have pulmonary or laryngeal disease. Tuberculosis is a life-threatening condition that requires treatment with a multidrug regimen for a minimum of 6 months.3
Tuberculosis has emerged as an enormous global public health epidemic. Worldwide, it is the second leading infectious cause of death, after HIV infection.4 The World Health Organization (WHO) has estimated that every year, about 9 million persons develop active tuberculosis, and more than 2 million persons die from the disease.5 Most of these deaths occur in resource-poor countries, where about 95% of the cases are found. Most cases of tuberculosis (5 to 6 million a year) occur in persons 15 to 49 years of age. Sub-Saharan Africa has the highest incidence (≥ 300 per 100,000 population annually), in part because of high rates of HIV coinfection [see Figure 1].4 For example, rates of HIV coinfection in patients with tuberculosis reportedly exceed 60% in Botswana, South Africa, Zambia, and Zimbabwe. The most populous countries of Asia have the largest numbers of cases: India, China, Indonesia, Bangladesh, and Pakistan together account for more than half the global burden, and 80% of new cases occur in 22 high-burden countries. In general, tuberculosis is declining in western and central Europe, North and South America, and the Middle East. By contrast, there have been striking increases in countries of the former Soviet Union and in sub-Saharan Africa, because of the HIV epidemic.4,5 It has been estimated that about two billion persons, or one third of the world's population, are infected with M. tuberculosis and thus are at risk for progression to active disease. There are major concerns that without increased attention to the disease and the development of new tools for treatment and control (e.g., an effective vaccine; new therapeutic agents and shorter treatment regimens; and improved diagnostics, including those for LTBI), the global tuberculosis epidemic will continue to worsen.
Figure 1. Incidence of global tuberculosis in 2003, per 100,000 population, as estimated by the World Health Organization.5
In the United States and western Europe, tuberculosis was a leading cause of death until early in the 20th century. The incidence of tuberculosis in the United States began to decline with improved living conditions and public health measures, even before the availability of effective chemotherapy. After the introduction of effective therapy in the mid-20th century, the incidence of tuberculosis decreased even further. Between 1985 and 1992, however, the United States experienced a resurgence of tuberculosis because of underfunding of tuberculosis control efforts (resulting in the decline of the public health infrastructure) and the emergence of the HIV epidemic. With increased attention and funding, the number of tuberculosis cases in the United States declined from a peak of 26,673 in 1992 to 14,511 in 2004 (a decline in rate from 10.5 to 4.9 cases per 100,000 population) [see Figure 2].6 The implementation of directly observed therapy (DOT) and improved infection control activities in hospitals and other institutional settings have contributed greatly to this decline.6
Figure 2. Number of tuberculosis cases reported in the United States, 1982–2004.6
Most tuberculosis cases in the United States now occur in foreign-born persons and in nonwhites.6 In 2004, tuberculosis case rates in African Americans born in the United States were more than eightfold higher than those in native whites. In the United States, rates are also much higher in Hispanics and Asians (especially foreign born) than in whites. The 2004 tuberculosis rate in foreign-born persons (22.5 cases per 100,000 population) was 8.7 times greater than that in United States-born persons (2.6 cases per 100,000 population).6 In 2003, the top five countries of birth of foreign-born patients with tuberculosis were Mexico (25.6%), the Philippines (11.6%), Vietnam (8.4%), India (7.7%), and China (4.8%). Molecular typing studies have suggested that in foreign-born persons in the United States, most tuberculosis cases result from the reactivation of LTBI, whereas in persons born in the United States, many cases (perhaps a third or more) result from recent transmission.7,8 Foreign-born persons may also be more likely to experience extrapulmonary tuberculosis.
Tuberculosis is not evenly distributed within the population. The disease is much more common in the economically disadvantaged, including the homeless and indigent inner-city residents.9 Tuberculosis is 200 times more likely to occur in HIV-positive persons than in HIV-negative persons.10 Persons with HIV coinfection are more likely to have extrapulmonary or disseminated tuberculosis, frequently along with pulmonary disease.
Other population groups that are at increased risk or that have a disproportionately high incidence of disease include immigrants (this is especially true during the first 5 years of arriving in the United States); substance abusers, including injection drug users and alcohol abusers; homeless persons; residents in certain institutional settings, such as correctional facilities and long-term care facilities; persons who are taking immunosuppressive drugs; and persons who have certain malignancies, diabetes mellitus, renal failure, or other debilitating conditions.1,11 Travelers to countries where tuberculosis is endemic are likely to be at somewhat increased risk for developing tuberculosis.12
During 2004, drug resistance in initial isolates of M. tuberculosis from persons with no previous history of treatment of tuberculosis was more common in foreign-born patients than in United States—born patients. Such isolates included strains of M. tuberculosis resistant to at least isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]). The rate of MDR-TB was higher in foreign-born than in United States—born persons (1.4% versus 0.6%), reflecting likely exposure to tuberculosis in countries where rates of MDR-TB are higher than in the United States. Rates of MDR-TB in the United States have decreased since the early 1990s.6 The decrease occurred in large part because of the dramatic reduction of MDR-tuberculosis cases in New York City: in the early 1990s, MDR-TB accounted for nearly a fifth of all tuberculosis cases in New York City.13,14 A key element of this decrease has been enhanced tuberculosis control through an improved public health structure and greater attention to treatment of tuberculosis, including greater use of DOT.
Etiology and Genetics
Tuberculosis is spread person to person via airborne droplet nuclei. These particles, which are 1 to 5 µm in diameter and contain M. tuberculosis, are generated by persons with pulmonary or laryngeal tuberculosis when they cough, sneeze, speak, or sing. Most secondary cases of tuberculosis occur in household members or other close contacts of the index case. Prolonged exposure to the index case increases the risk of becoming infected, although on occasion, transmission can occur after brief exposures. Infectivity is greatest in patients whose sputum smear is AFB positive; this group may include those with cavitary disease or tuberculosis of the larynx. Coughing further enhances shedding. Persons with tuberculosis who are AFB smear-negative (and culture positive) are thought to be less infectious than AFB smear-positive patients but may still transmit tuberculosis.15
Some patients may have an increased susceptibility to tuberculosis that is genetically determined. For example, concordance for tuberculosis is significantly higher in monozygous twins (65% to 85%) than in dizygous twins (25% to 35%).16 African Americans and Native Americans may be more susceptible than whites to M. tuberculosis infection.17 Other studies have suggested that patients carrying mutations in the receptors for interferon gamma (IFN-γ) and interleukin-12 (IL-12) are at increased risk for severe atypical mycobacterial and disseminated bacillus Calmette-Guérin (BCG) infections.18 Several associations have also been made with variants of genes thought to be important in the pathogenesis of tuberculosis, including NRAMP1 and genes that code for the vitamin D receptor (VDR), IL-10, tumor necrosis factor-α (TNF-α), and IL-1. Four polymorphic-derived deletions or point mutations of the NRAMP1 gene have been associated with increased susceptibility to tuberculosis in Gambia and in other populations in Japan, Guinea, and Korea.18 Associations between genetic polymorphisms and tuberculosis susceptibility differ according to ethnic origin,19 but the extent to which genetic polymorphisms contribute to the global burden of disease has not been fully elucidated, in part because of the great difficulty of separating lifelong environmental influences from genetic predisposition.4
The pathogenesis of tuberculosis is unique among infectious diseases because of the highly variable but sometimes long latency period between infection and clinical illness. Although a single tubercle bacillus theoretically can cause infection, it must first bypass the upper airway defense mechanisms and lodge in the distal pulmonary alveoli. Infectious droplet nuclei are inhaled and lodge in the alveoli in the distal airways, whereas larger particles are usually trapped in the upper respiratory tract. M. tuberculosis is taken up by alveolar macrophages, and this can result in infection with the organism. After exposure to someone with infectious tuberculosis, the exposed person experiences one of four potential outcomes [see Figure 3]: (1) no infection (as measured by a negative tuberculin skin test); (2) infection, with rapid progression to active disease (primary tuberculosis); (3) LTBI, in which immune mechanisms prevent the progression to active disease; and (4) LTBI followed by subsequent reactivation and development of active tuberculosis months to years later.20,21
Figure 3. Natural history of Mycobacteria tuberculosis infection.96 The innate immune system provides the first line of defense against M. tuberculosis and often prevents infection. Results of tuberculin skin testing (TST) are negative at this stage. Subsequent control of tuberculosis is provided by the adaptive immune system; this results in positive TST results. In 90% of cases, host defenses kill the great majority of organisms, but some M. tuberculosis bacilli persist within macrophages, resulting in latent infection. Reactivation of disease occurs in 5% to 10% of patients, sometimes years later. Less than 5% of patients experience primary progressive disease.
The immune response mounted against M. tuberculosis is multifaceted and complex. Effective innate immune responses to M. tuberculosis are clearly important, given that a significant proportion of persons exposed to M. tuberculosis do not become infected after exposure. For example, contact investigations have shown that at most only 30% to 50% of persons with heavy exposure to someone with tuberculosis will become infected, as demonstrated by conversion on tuberculin skin testing. If infection does occur, M. tuberculosis multiplies within alveolar macrophages and subsequently disseminates through blood and lymphatic pathways to areas of high oxygen tension. Hence, the lung apices are a common repository. Other frequently infected areas include the renal cortex, the vertebral column, and the metaphyseal ends of long bones. After 6 to 8 weeks, an adaptive cell-mediated immunity is well established, and results of tuberculin skin testing become positive.
The cell wall of Mycobacterium species has a high lipid content because of the presence of mycolic acids. Therefore, mycobacteria are impermeable to, and undetectable with, the usual bacteriologic stains, such as Gram stain. Mycobacteria, including M. tuberculosis, are acid-fast bacilli (AFB); the lipoid capsule of the acid-fast organism takes up carbol-fuchsin and resists decolorization with a dilute acid rinse.
A wide range of immune components are involved in an effective response against M. tuberculosis. These components include T cells (CD4+and CD8+, which are activated in response to M. tuberculosis infection), cytokines (including IFN-γ, IL-12, TNF-α, and IL-6), and macrophages.21 The macrophage is felt to play a key role in the control of M. tuberculosis infection; the organism can multiply within resting macrophages, but it can be inhibited or killed when the macrophage is activated.21
Cytokines produced by T cells contribute to the immune response in a multitude of ways, such as by activating macrophages, the host cell in which M. tuberculosis primarily resides. CD4+ and CD8+ T cells can also be cytotoxic for infected cells. CD4+ T cells play a key role in the immune response, as demonstrated by a marked increase in susceptibility to tuberculosis in HIV-infected persons whose CD4+ T cells are depleted. The predominance of T helper type 1 (Th1) cell response is associated with protection and control of tuberculosis infection, whereas Th2 responses predominate in patients who are unable to contain the infection and who develop active disease. Th1 responses are markedly impaired in HIV-infected persons, especially those with low CD4+ T cell counts and advanced disease. IL-12 is an important cytokine in controlling M. tuberculosis. It is produced by activated macrophages and drives development of a Th1 response, which stimulates CD4+ T cells to release IFN-γ. IFN-γ alone is insufficient to control M. tuberculosis. IFN-γ is, however, a crucial element in the control of tuberculosis, and it also stimulates the macrophage to release TNF-α, which is important in granuloma formation and control of the extent of infection. The importance of TNF-α has been demonstrated by the marked increase in risk of progression to active tuberculosis, including extrapulmonary and disseminated disease, in patients with LTBI who were treated with the anti-TNF agent infliximab for rheumatologic and immunologic diseases.22
After exposure to and infection with M. tuberculosis, most persons develop LTBI [see Figure 3]. This chronic infection stimulates formation of granulomas in the lungs or other tissues; these granulomas consist of lymphocytes (CD4+ and CD8+ T cells, as well as B cells) that surround macrophages, some of which contain M. tuberculosis, as well as other cells such as fibroblasts. The development of a granuloma serves to limit the spread of the infection by walling off the organisms from the rest of the lung or other organ tissue. After the development of cell-mediated immunity, host defenses are able to respond to M. tuberculosis; the great majority of the organisms are killed, and the mycobacterial load is greatly reduced [see Figure 3]. However, host defenses are not able to entirely eradicate all organisms; someM. tuberculosis persist within macrophages, and thus the possibility remains for reactivation of disease. The mechanism of resistance by M. tuberculosis, persistence in macrophages over many years, and reactivation is poorly understood.
As a result of host defenses, most patients experience complete healing of these initial tuberculous lesions. In patients whose primary lesions heal, the chest radiograph may be normal or it may show focal calcifications. The primary lower lobe lesion and its draining node may be recognized radiographically as the Ghon complex; apical calcifications (Simon foci) may be present. Although inactive, these lesions contain small numbers of dormant but viable tubercle bacilli, and breakdown of the lesions can lead to reactivation of infection.
In about 5% to 10% of immunocompetent persons infected with M. tuberculosis, LTBI progresses to active disease.23 The risk of reactivation is greatest within the first 2 years of the initial infection, but there is a subsequent lifetime risk of up to 5% for reactivation, which can occur many decades after initial infection.24 Immune compromise increases the risk of progression to active disease. HIV infection is the greatest single risk factor for progression to active disease in adults. Progression from LTBI to active disease takes place at a rate of about 10% a year in HIV-infected persons2; those with low CD4+ T cell counts may be incapable of controlling infection and may develop active disease rapidly after exposure and infection. Other medical conditions that predispose to the development of active disease include diabetes mellitus, renal failure, certain malignancies, cancer chemotherapy, therapy with corticosteroids or other immunosuppressive drugs (including TNF-α inhibitors such as infliximab, etanercept, and adalimumab), transplantation, and malnutrition. Tuberculosis may also develop in patients without these underlying risk factors, however, for reasons that are not well understood. In some patients, including those who are infected with HIV and those living in regions where tuberculosis is hyperendemic, exogenous reinfection can occur.25 In the United States, however, molecular epidemiologic investigations indicate that most recurrences result from relapse of disease rather than reinfection with a different strain of M. tuberculosis.26
Forms of Tuberculosis
In the United States, about 80% of tuberculosis cases occur as pulmonary disease.27 Pulmonary tuberculosis can be divided into primary tuberculosis (i.e., developing soon after infection) and secondary tuberculosis (i.e., developing after a variable period of LTBI). Secondary disease is also known as postprimary or reactivation tuberculosis.
Primary tuberculosis is frequently localized to the middle and lower lung zones and is accompanied by hilar or paratracheal lymphadenopathy. In some cases, the lesion heals spontaneously and may later be evident on chest x-ray as a small calcified nodule (Ghon lesion). Primary disease was once most common in young children, but it has been seen with increasing frequency in adults who are debilitated or immunosuppressed, especially from HIV infection. Primary tuberculosis typically manifests as one of four broad syndromes: a syndrome resembling atypical pneumonia; tuberculous pleuritis with pleural effusion; direct progression to upper lobe disease; and progression to extrapulmonary disease. Uncommon manifestations of primary tuberculosis include erythema nodosum and other hypersensitivity reactions, such as reactive arthritis (Poncet disease).
The most common form of primary tuberculosis is a syndrome that is similar to atypical pneumonia, with fever and nonproductive cough. The chest radiograph may show unilateral, lower lobe, patchy parenchymal infiltrates; paratracheal or hilar adenopathy; or both. Although patients with this form of tuberculosis should receive full antituberculous chemotherapy, the symptoms may resolve even without therapy. Resolution without therapy would not be expected in most immunocompromised persons, however.
Tuberculous pleuritis with pleural effusion results from penetration of bacilli into the pleural space from an adjacent subpleural focus. This can occur early in the course of infection and may represent a hypersensitivity response to only a few organisms in the pleural space.28 In immunocompetent patients, this form of tuberculous pleuritis may go unnoticed, and the process may resolve spontaneously. Other patients, however, including both immunocompetent and immunosuppressed persons, may have an acute illness with high fever, cough, and pleuritic chest pain; if the effusion is large, dyspnea may also occur. Chest radiography often reveals unilateral pleural effusion, generally without identifiable parenchymal lesions. The tuberculin skin test is strongly positive in the majority of immunocompetent persons with tuberculous pleurisy, but it is positive in only about 40% of HIV-infected patients who have the syndrome.
Direct progression of primary tuberculosis to upper lobe disease is relatively rare. Progression of primary infection to extrapulmonary tuberculosis (also known as progressive primary tuberculosis) was once most common in young children, who presented with cervical adenitis, miliary tuberculosis, or tuberculous meningitis; currently, it is most often observed in persons with HIV infection.
Reactivation pulmonary disease is the most common clinical form of tuberculosis. Classic symptoms include cough, fever, and night sweats. Symptoms usually begin insidiously and progress over a period of several weeks or even months before diagnosis. Cough may be nonproductive, or it may gradually become productive. Dyspnea is relatively uncommon in the absence of underlying chronic lung disease. Systemic symptoms, which are often prominent, include fever, anorexia, weight loss, night sweats, and malaise. Fever is reported in 37% to 80% of patients with tuberculosis28; low-grade fevers are typical, but some patients have high temperatures and even chills. However, in some patients with pulmonary tuberculosis, these classic symptoms may be absent, making diagnosis more difficult.29 In addition, in patients with advanced disease who present with respiratory failure, tuberculosis may not be considered in the differential diagnosis, and as a result, the diagnosis of pulmonary tuberculosis may be delayed.
Hemoptysis from endobronchial erosion may occur in tuberculosis; it is usually minor but denotes advanced disease. Massive hemoptysis resulting from the erosion of a pulmonary artery by an advancing cavity (Rasmussen aneurysm) is a terminal event that was occasionally seen in the prechemotherapy era but is currently rare. Hemoptysis may also occur in patients with inactive disease (e.g., after completion of therapy) who develop Aspergillus superinfection of a residual cavity (aspergilloma).
Physical Examination Findings
Physical examination is typically of limited usefulness in differentiating tuberculosis from other pulmonary infections. Some patients with tuberculosis have no abnormalities that are detectable by chest examination, whereas others have rales in the involved areas. Coarse rhonchi may evolve as secretions increase. Bronchial breath sounds may be present in areas of consolidation.
A chest radiograph is an important tool that may suggest the diagnosis of pulmonary tuberculosis. Typical features include unilateral or bilateral infiltration; cavitation is common in patients with reactivation disease [see Figure 4]. The most frequent sites of involvement in reactivation disease are, in decreasing order, the apical and posterior segments of the right upper lobe, the apical-posterior segment of the left upper lobe, and the superior segments of the lower lobes. Lower-zone disease is seen at presentation in fewer than 15% of HIV-seronegative adults; it is much more common in HIV-infected persons (e.g., as part of primary disease) and is somewhat more common in patients with diabetes mellitus and in patients with prominent peribronchial and endobronchial involvement. Chest radiographs appear normal in about 10% of persons with tuberculosis and HIV coinfection,30 whereas normal chest radiographs are extremely rare in HIV-seronegative persons with pulmonary tuberculosis.
Figure 4. (a, b) Upper-lobe cavitary pulmonary disease is evident on chest radiographs from patients with reactivation pulmonary tuberculosis. Chest radiographs from HIV-infected patients with proven culture-confirmed tuberculosis demonstrate so-called atypical findings, including (c) a right middle-lobe infiltrate; (d) prominent hilar adenopathy on the right, with clear lung fields; and (e) bilateral interstitial changes. These findings are consistent with primary disease.
Computed tomography is more sensitive than chest radiography. CT scans may show nodular or branching linear centrilobular lesions in very early disease and in patients with tuberculosis and an apparently normal chest radiograph.
Tuberculosis may affect any organ system. Extrapulmonary tuberculosis results from hematogenous dissemination of tubercle bacilli with incomplete immunologic control of the disease, either during primary infection or as a result of reactivation from a site of latent infection.
In order of frequency, extrapulmonary tuberculosis involves the lymph nodes, the pleura, the genitourinary tract, bone and joints, the meninges, and the peritoneum. Extrapulmonary tuberculosis, including miliary (disseminated) disease, is being seen more frequently because of its increased prevalence in HIV-infected persons. It is not unusual for HIV-infected patients with tuberculosis to have concomitant pulmonary and extrapulmonary disease. Very young children, immunocompromised patients, and perhaps patients born in foreign countries are also at increased risk for extrapulmonary disease, as are patients with LTBI who have been treated with TNF-α inhibitors such as infliximab, etanercept, and adalimumab.22
Tuberculosis of the lymph nodes is the most common form of extrapulmonary tuberculosis, accounting for up to 40% of extrapulmonary cases. It is frequently encountered in HIV-infected persons. Tuberculous lymphadenitis is also seen in young children; women, especially nonwhites, also appear to be at increased risk. The cervical nodes (posterior and anterior) and supraclavicular lymph nodes are most commonly affected. In addition, mediastinal lymphadenitis may appear with early or primary disease, because these nodes drain the lung. HIV-seronegative patients are often afebrile and present with slowly enlarging, painless mass lesions. Patients with HIV infection or AIDS may be febrile. The diagnosis can be established by fine-needle aspiration or lymph node biopsy. Therapeutic lymph node excision is not indicated except in unusual circumstances. For large lymph nodes that are fluctuant and that appear to be about to drain spontaneously, aspiration or incision and drainage appear to be beneficial, although this approach has not been examined systematically.3
Pleural tuberculosis typically occurs when a few organisms from the lungs gain access to the pleural space and, in the presence of cell-mediated immunity, cause a hypersensitivity response. Physical findings are those of a pleural effusion: dullness to percussion and absence of breath sounds. A chest radiograph usually demonstrates a unilateral pleural effusion. Thoracentesis is required for diagnosis; findings include an exudative effusion with a protein concentration that is greater than 50% of the serum level, a normal to low glucose level, and the presence of white blood cells, most of which are lymphocytes and mononuclear cells rather than neutrophils. A pleural biopsy can greatly increase the likelihood of obtaining a positive culture (increasing the yield to greater than 80%) compared with pleural fluid culture alone.
Tuberculous empyema has become much less common than it was in the prechemotherapy era. It results from the rupture of a lung cavity into the pleural space or from a bronchopleural fistula. The rupture of a cavity results in the discharge of a large number of organisms into the pleural space; in addition, parenchymal disease is often present on chest radiograph, and a pyopneumothorax with an air-fluid level may also be visible. The effusion is purulent and thick and contains large numbers of white blood cells, predominantly lymphocytes. Treatment consists of drainage (often requiring a surgical procedure) and antituberculous chemotherapy. Surgery, when needed, should be undertaken by experienced thoracic surgeons.3
Genitourinary tuberculosis accounts for about 15% of extrapulmonary tuberculosis cases and may involve any part of the genitourinary tract. It usually results from hematogenous seeding after primary infection. Historically, it has occurred years after primary infection. Local symptoms predominate: dysuria, hematuria, and frequent urination are common, and flank pain may also be noted.28 Renal tuberculosis often has an insidious onset and subtle symptoms; consequently, advanced destruction of the kidneys may have taken place by the time the diagnosis is established. The urine sediment is abnormal in about 90% of patients with renal tuberculosis; urinary findings include pyuria, hematuria, or both. Imaging studies may reveal structural abnormalities; calcification, cavitation, and ureteral strictures and fibrosis suggest tuberculosis, whereas calyceal dilatation, cortical scarring, and papillary necrosis are nonspecific. A CT scan is as useful as an intravenous pyelogram for visualizing advanced urinary tract tuberculosis; ultrasonographic studies are less accurate. The finding of so-called sterile pyuria (i.e., acidic urine that contains white blood cells but in which no bacterial organisms are isolated on routine urine culture) should prompt culture of the urine for mycobacteria. AFB smears should be performed on urine, although the yield is low compared with that of AFB urine culture; nucleic acid amplification (NAA) testing (see below) of urine may provide a more rapid diagnosis than AFB culture but is not a substitute for a culture.31
Genital tuberculosis is more common in women than men. In women, genital involvement may occur without renal tuberculosis; pelvic pain, menstrual irregularities, and infertility are possible presenting complaints. Occasionally, ovarian masses from tuberculosis may be mistaken for ovarian tumors. The differential diagnosis may also include pelvic inflammatory disease. The physical examination may be normal or may reveal an adnexal mass. Endometrial curettage, cervical biopsy, and laparoscopic exploration are all useful as diagnostic procedures. Surgery is often needed for diagnosis of tubo-ovarian abscesses or pelvic peritonitis.
Male genital tuberculosis can result from hematogenous seeding or can spread from infected urine after reactivation in the upper urinary tract. About 50% of male patients with genital tuberculosis also have renal tuberculosis; this is a higher proportion than is found in women with genital tuberculosis. Male patients may present with slowly enlarging mass lesions of the epididymis, prostate, or seminal vesicles. Genital tuberculosis in both men and women responds well to chemotherapy.
Tuberculosis can affect any bone or joint, but involvement of the spine (Pott disease) is the most common type of skeletal tuberculous disease, accounting for up to 50% of cases.32 The thoracic spine is the most common site of spinal tuberculosis. Upper thoracic vertebral body involvement is more common in children, whereas lower thoracic and upper lumbar disease is more common in adults. Often, two or more vertebral bodies are involved; vertebral body involvement can lead to disease of an adjacent intervertebral disk and paraspinous abscesses. With advanced disease, collapse of vertebral bodies may result in kyphosis (gibbus) or even paraplegia.33
The usual presenting symptom of skeletal tuberculosis is pain. Patients with joint involvement can have swelling of the joint and limitation of motion. Tuberculous joint involvement can sometimes become apparent after trauma to the joint. Because of the subtle nature of the symptoms, especially initially, diagnosis of skeletal and joint disease can be delayed for long periods.
Radiographically, tuberculosis of bones appears as an array of destructive osteolytic lesions with relatively little reactive bone formation. CT and MRI are useful imaging tests [see Figures 5a, 5b, and 5c]. Definitive diagnosis requires biopsy and culture of affected bone or, in patients with joint involvement, arthrocentesis with culture of synovial fluid. Tuberculous arthritis is characteristically a chronic, slowly progressive, destructive monoarticular process. The synovial fluid has a high protein level, a low glucose level, and a poor mucin clot. The white blood cell count is variable but is typically in the range of 10,000 to 20,000/µl; neutrophils often predominate. AFB smears are rarely positive because of the paucibacillary nature of this form of tuberculosis, but culture and biopsies of the synovium are helpful.
Figure 5. (a) Plain Film and (b) MRI from a patient with skeletal tuberculosis (Pott disease) demonstrate radiographic findings of vertebral tuberculosis: anterior disk destruction and collapse, loss of vertebral body height, and disk-space narrowing. Extensive anterior vertebral body destruction can lead to anterior angulation of the spine, producing the characteristic gibbus deformity seen on the MRI. (c) CT scan from a patient with vertebral osteomyelitis shows a psoas abscess, which is not uncommonly associated with vertebral tuberculosis.
Tuberculous rheumatism (Poncet disease) is a rare form of acute polyarthritis that results from a hypersensitivity reaction rather than direct synovial infection. Prosthetic joint tuberculosis and tubercular tenosynovitis are uncommon. For skeletal tuberculosis, tumor is the major consideration in the differential diagnosis, and fungal and pyogenic infections are additional considerations.
Randomized trials in patients with spinal tuberculosis demonstrated no additional benefit of surgical debridement or radical operation (i.e., resection of the spinal focus and bone grafting) in combination with chemotherapy compared with chemotherapy alone.34 Myelopathy with or without functional impairment most often responds to chemotherapy. However, in some circumstances, surgery appears to be beneficial and may be indicated. Indications for surgery include the failure to respond to chemotherapy in conjunction with evidence of ongoing infection; the need for spinal cord decompression in patients with persistent or recurrent neurologic deficits; or instability of the spine.3
Although infrequent, tuberculous pericarditis is a very serious form of tuberculosis. Infection of the pericardium can result from either hematogenous dissemination of bacilli or contiguous spread from lung or mediastinal nodes. Pathologically, the disease progresses from inflammation to effusion and eventually to fibrous organization. Symptoms are nonspecific and initially include the insidious onset of fever, weight loss, and night sweats. Subsequently, cardiopulmonary symptoms occur; these include cough, dyspnea, orthopnea, ankle swelling, and chest pain. Physical examination may disclose a pericardial rub or a pulsus paradoxus. A chest x-ray may show a pericardial effusion.
The diagnosis of tuberculous pericarditis depends on direct examination of pericardial fluid or tissue. The pericardial fluid is turbid or hemorrhagic. White blood cell counts typically range from 5,000 to 10,000/µl; lymphocytes are predominant. High protein levels and low glucose levels are typical. AFB smears or cultures of pericardial fluid are positive in about half of cases, but pericardial biopsy with culture has a higher diagnostic yield. The major differential diagnosis includes idiopathic, bacterial, or viral pericarditis and neoplasm.
If left untreated, tuberculous pericarditis has a high mortality, and constriction eventually occurs in many survivors. Surgery is indicated if clinical tamponade progresses or recurs despite repeated pericardiocentesis [see 1:XIII Diseases of the Pericardium, Cardiac Tumors, and Cardiac Trauma]. However, in the absence of tamponade, medical therapy is generally sufficient. Antituberculous chemotherapy with four drugs should be started immediately and supplemented initially with corticosteroids; cortico-steroids should be tapered over a 12-week period [see Treatment, below]. Corticosteroids have been useful in reducing mortality from tuberculous pericarditis and enhancing clinical response to therapy, but they do not appear to reduce progression to constriction or the need for pericardiectomy.
Central Nervous System Disease
Tuberculous meningitis is a particularly devastating manifestation of tuberculosis, with high mortality (about 40%) and morbidity.35 Children younger than 5 years of age and HIV-infected persons are at increased risk for tuberculous meningitis. The clinical manifestations, laboratory findings, and outcomes are similar in patients with and without HIV infection.35,36 Tuberculous meningitis may result from hematogenous seeding of the meninges, or it can be caused by the breakdown of an old submeningeal granuloma with rupture into the subarachnoid space.
Clinical manifestations of tuberculous meningitis result both from the presence of M. tuberculosis and from the inflammatory host immune response.4 Clinical manifestations may include headache, fever, altered mental status, cranial nerve findings, and nuchal rigidity. The intense inflammatory reaction is most prominent at the base of the brain and can have three effects: direct compression of neural tissues, especially cranial nerves; vasculitis, leading to areas of infarction; and obstruction of the free flow of cerebrospinal fluid, leading to cerebral edema, hydrocephalus, or subarachnoid block. CT or MRI may demonstrate basal meningeal enhancement and hydrocephalus. Up to 50% of patients with tuberculous meningitis have abnormalities on chest radiograph indicating old healed tuberculosis or current pulmonary disease or miliary disease. Lumbar puncture is an essential diagnostic test and should be carried out if meningeal signs are present. The CSF opening pressure is usually elevated but on occasion may be normal. CSF examination generally reveals an elevated white blood cell count (often in the range of 100 to 1,000/µl), typically with a lymphocyte predominance, although in early disease, neutrophils can predominate; CSF protein is elevated and CSF glucose level is usually decreased. Acid-fast smears of CSF are insensitive; they are positive in only about 10% of patients with culture-confirmed tuberculous meningitis.35 CSF cultures may be eventually positive in up to 75% of cases. NAA tests (see below) may be positive but are insensitive in diagnosing tuberculous meningitis; a negative NAA test on CSF does not rule out tuberculous meningitis.37 The principal considerations in the differential diagnosis include cryptococcal meningitis and other less common forms of fungal meningitis (e.g., histoplasmosis, blastomycosis, coccidioidomycosis), viral meningitis or encephalitis (e.g., from herpes simplex virus, enteroviruses, West Nile virus, and other arboviruses), and, if antibiotics have been given, partially treated bacterial meningitis [see 7:XXXVI Bacterial Infections of the Central Nervous System]. Noninfectious diseases in the differential diagnosis include carcinomatous meningitis, neurosarcoidosis, and CNS vasculitis.
Initiation of empirical therapy is crucial for patients with presumed tuberculous meningitis. Corticosteroids are indicated as adjunctive therapy (see below). Without therapy, tuberculous meningitis is universally fatal. The prognosis is worse in young children and in patients who present with altered mental status.38
Less common forms of CNS tuberculosis include radiculomyelitis and other infections of the spinal cord or epidural space39; and cerebral tuberculomas,40 which typically present as slowly enlarging mass lesions. Tuberculomas may be initially misdiagnosed as brain tumors before surgical exploration and brain biopsy confirm the proper diagnosis. Tuberculomas may also develop during the course of therapy for tuberculous meningitis; their appearance does not necessarily represent treatment failure.
Tuberculosis can involve the peritoneum or any intra-abdominal organ. The clinical manifestations depend on the area of involvement. Peritoneal disease is the most common type of abdominal tuberculosis. In the gut, tuberculosis may occur in any location from the mouth to the anus but is most common in the terminal ileum and cecum; other portions of the colon and rectum are less frequently involved.28Peritoneal tuberculosis may be secondary to hematogenous spread or, in women, to genital tuberculosis. Ileocecal and anorectal tuberculosis likely arise from the ingestion of tubercle bacilli in association with pulmonary disease. In peritoneal tuberculosis, the onset may be insidious; pain is a frequent presenting manifestation, often accompanied by abdominal swelling and increasing girth, fever, weight loss, and anorexia. Pulmonary tuberculosis is often not present in patients with peritoneal tuberculosis. Because peritoneal tuberculosis may occur in patients with preexisting disorders, including hepatic cirrhosis with ascites, the symptoms of tuberculosis may be obscured.28 The findings of ascites, abdominal tenderness, and fever should prompt an evaluation for infection, which should include paracentesis. Examination of peritoneal fluid generally shows an elevation in the white blood cell count with a lymphocytic predominance, elevated protein levels, and decreased glucose levels. AFB smears and cultures of peritoneal fluid are often negative unless extremely large volumes of fluid are examined. Laparoscopy with biopsy is recommended if tuberculosis is suspected; it has a much higher diagnostic yield. The differential diagnosis includes carcinomatosis, lymphoma, and cirrhosis. Tuberculous enteritis often involves the ileocecal region and may mimic Crohn disease or a malignancy. CT scanning and barium examinations are helpful, but colonoscopy and biopsy are required for diagnosis.
Miliary (Disseminated) Tuberculosis
Miliary, or disseminated, tuberculosis is defined as involvement of many organs simultaneously. It can occur as a result of primary progressive disease or reactivation of latent infection.4 Miliary tuberculosis is both a radiologic and pathologic term used to describe the hematogenous dissemination of M. tuberculosis. Radiologically, the term miliary refers to the pattern often seen on chest radiography, which is described as resembling millet seeds (e.g., a small reticulonodular pattern rather than an infiltrate). Not all patients with disseminated disease have pulmonary involvement, however.
The epidemiology of miliary or disseminated tuberculosis has changed dramatically over time. The incidence of miliary disease decreased markedly after the introduction of effective chemotherapy for tuberculosis. However, the advent of HIV/AIDS brought an increase in the number of cases. Miliary tuberculosis was once a disease primarily of children but now occurs primarily in HIV-infected persons, especially those with low CD4+ T cell counts; it is also occasionally seen in elderly persons or other immunocompromised patients.
The onset of miliary tuberculosis is usually subacute. Symptoms often progress over a period of 1 to 4 months before diagnosis. Fever, anorexia, and weight loss occur in most patients. Respiratory symptoms occur in about half of patients with miliary disease, but hemoptysis is quite rare. Many other symptoms may appear; headache is particularly important because it may reflect coexisting tuberculous meningitis. Variant presentations, which account for a small percentage of cases, include cryptic miliary tuberculosis, in which patients have normal chest x-rays and exhibit problems typical of fever of undetermined origin [see 7:XXIV Hyperthermia, Fever, and Fever of Undetermined Origin]. An uncommon occurrence is fulminating miliary disease, which can have a sepsislike picture that includes respiratory failure, acute respiratory distress syndrome, disseminated intravascular coagulation, and multiorgan failure; often, tuberculosis is not considered early in this diagnosis.41,42
The physical examination in patients with miliary tuberculosis usually yields nonspecific results. Various pulmonary findings are seen in up to 50% of observed cases, hepatomegaly is seen in 30%, and splenomegaly or lymphadenopathy in 15%. Choroidal tubercles are less common, but they are diagnostically useful if present. Laboratory findings are often nonspecific. The white blood cell count may be normal, but dramatic abnormalities have been well documented in this disorder and may range from pancytopenia to leukemoid reactions. Abnormal liver function test results, especially elevation of the alkaline phosphatase level, occur in 30% of cases. Hyponatremia is less common but, if present, should raise the possibility of inappropriate antidiuretic hormone secretion or adrenal insufficiency. AFB sputum smears are positive in only a minority (no more than 30%) of patients who have a miliary pattern on chest radiography. The use of fiberoptic bronchoscopy, bronchial brushings, and transbronchial biopsy to collect specimens may enhance the accuracy of bacteriologic studies, providing confirmation of the diagnosis in patients with miliary disease who have abnormal chest x-rays but negative sputum smears. Liver biopsy is especially helpful, revealing granulomas and providing positive cultures in about 60% of patients. Bone marrow biopsy is positive in about one third of all patients with miliary tuberculosis and has an even higher yield in those with hematologic abnormalities. The differential diagnosis in miliary tuberculosis includes histoplasmosis and other mycotic infections, sarcoidosis and other connective-tissue diseases, and malignant disorders.
Disseminated or miliary disease is fatal without chemotherapy; even with appropriate chemotherapy, mortality may be as high as 20%.43,44Adverse prognostic features include the presence of meningitis, extremes of age (i.e., old age and early childhood), delay in presentation, and the presence of underlying diseases. Clinical improvement with treatment is often very slow, and fever can persist for 1 to 3 weeks.
Other Forms of Extrapulmonary Tuberculosis
Other, less common forms of extrapulmonary tuberculosis include infection of the eye, skin (lupus vulgaris), upper respiratory tract (especially the larynx), pancreas, ear, and adrenal gland. Adrenal disease (often occurring with miliary or disseminated disease) is particularly important to consider and often is a manifestation of advanced disease presenting as signs of adrenal insufficiency. Onset of adrenal tuberculosis is usually insidious but can be acute; the disease should be considered in all patients with active or remote tuberculosis who are doing poorly, particularly if hypotension, hyponatremia, or hyperkalemia is present. Congenital tuberculosis is rare but can result from transplacental spread of M. tuberculosis to the fetus or from ingestion of contaminated amniotic fluid. Affected infants have disseminated disease, including involvement of the liver, spleen, lymph nodes, and other organs.
TUBERCULOSIS IN HIV-INFECTED PATIENTS
The interaction between HIV and M. tuberculosis is synergistic, each increasing the pathogenicity of the other.45 HIV infection increases the susceptibility to developing active disease after infection with M. tuberculosis, and immune activation by M. tuberculosis increases HIV plasma viremia and appears to increase the rate of HIV disease progression and mortality.46 HIV infection may increase the rate of tuberculosis after treatment completion or cure, in part because of an increased risk of reinfection, especially in highly endemic areas.47Dramatic point-source outbreaks of tuberculosis have been reported to occur where HIV-infected persons congregate, both in the United States and in other countries.48,49 Many of these outbreaks have occurred in health care settings; in the United States, subsequent outbreaks have been prevented by implementation of effective tuberculosis infection control measures.23,50 Such outbreaks will likely continue to occur in resource-poor areas where such measures have not been implemented. In the United States, HIV-related tuberculosis outbreaks have also been reported in other institutional settings, such as correctional facilities and homeless shelters.51,52
Tuberculosis can occur at any stage of HIV infection, but the clinical presentation is affected by the level of immunosuppression. Because M. tuberculosis is more virulent than opportunistic pathogens encountered in persons with HIV/AIDS, tuberculosis may be seen at higher CD4+T cell counts (i.e., > 200 cells/µl) than are generally seen with other opportunistic infections. When tuberculosis occurs early in the course of HIV infection, before severe immunosuppression has developed, the clinical and radiographic features resemble tuberculosis in patients who are HIV seronegative. In patients with more advanced HIV disease and lower CD4+ T cell counts, M. tuberculosis tends to produce disease that is more widespread and severe than conventional tuberculosis and that has so-called atypical features [see Figure 4]. With progressive immunodeficiency, extrapulmonary involvement becomes increasingly common.
Pulmonary involvement remains common at all stages of HIV disease; however, the radiographic pattern is very different in persons with advanced immunodeficiency, in whom the most common abnormalities are intrathoracic adenopathy, focal lower or middle lobe infiltrates, and diffuse miliary or nodular infiltrates. This pattern is consistent with a primary tuberculosis-like pattern. Overall, sputum AFB smears are less likely to be positive in patients with pulmonary disease and HIV coinfection than in noninfected patients, and HIV-infected patients are less likely to have cavitary disease. In one study, 8% of HIV-infected patients with pulmonary tuberculosis had normal chest radiographs.30Those with advanced HIV/AIDS frequently have concomitant pulmonary and extrapulmonary or disseminated tuberculosis. Up to 60% of HIV-infected patients with low CD4+ T cell counts (< 200/µl) who develop tuberculosis have involvement of one or more extrapulmonary sites, including diffuse lymphadenitis, disseminated pleural and pericardial disease, or multiorgan involvement. Mycobacteremia and meningitis are also common in patients with advanced HIV infection.
Not surprisingly, given the atypical features of pulmonary tuberculosis in HIV-infected patients, particularly those with low CD4+ T cell counts, delayed or missed diagnoses have been commonly reported. Thus, a high index of suspicion is crucial in making an appropriate diagnosis. The keys to the diagnosis of HIV-related tuberculosis are knowledge of the epidemiology of tuberculosis, recognition of the ways that immunodeficiency changes the clinical presentation, and an assiduous effort to obtain specimens for mycobacterial smear and culture.53
Targeted Testing for LTBI
The decrease in tuberculosis cases in the United States has brought a renewed focus on the treatment of LTBI as an important tuberculosis control strategy.54 Targeted tuberculin testing for LTBI is a critical component of this strategy. Such testing identifies persons who are at high risk for developing tuberculosis and consequently would benefit from treatment of LTBI. (This type of treatment was previously called preventive therapy or chemoprophylaxis.) In immunocompetent persons, the lifetime risk of progression from latent infection with M. tuberculosis to active disease ranges from 5% to 10%; by contrast, in persons infected with HIV, the annual risk of disease progression is 10%.
HIV/AIDS is clearly the greatest risk factor for progression to active tuberculosis after infection with M. tuberculosis. Other risk factors include infection within the past 2 years (e.g., as indicated by a history of contact with a person known to have tuberculosis), injection drug use, silicosis, and certain other medical conditions and circumstances (e.g., diabetes mellitus, renal failure, certain malignancies, gastrectomy or jejunoileal bypass, solid-organ transplantation, or the use of immunosuppressive drugs; identification of LTBI is of particular importance in patients who are to be treated with TNF-α inhibitors such as infliximab, etanercept, or adalimumab).22 The risk for progression is also higher in immigrants who have arrived in the United States within the past 5 years from areas where there is a high incidence of tuberculosis; in racial or ethnic minorities; in children 4 years of age or younger; and in children and adolescents who are exposed to adults at high risk.
TUBERCULIN SKIN TESTING
Until recently, the tuberculin skin test was the only available diagnostic test for LTBI, and it remains the most commonly used test. Tuberculin skin testing has a number of important limitations (see below), and new, improved diagnostic tests for LTBI (including those that can distinguish between infection with M. tuberculosis and M. bovis BCG [BCG vaccination]) are urgently needed.55 It is hoped that tuberculin skin testing will be replaced with improved diagnostic tests in the coming years.
Tuberculin skin testing should be performed only on persons at increased risk for tuberculosis.1 False positive results are common when the test is used in populations with a low prevalence of tuberculosis.23,28 False positives also occur in persons vaccinated with BCG vaccine or in persons who are sensitized to environmental mycobacteria. False negative reactions are common in immunosuppressed persons and in those with overwhelming tuberculosis disease. In addition, testing is inconvenient, in that patients must return 48 to 72 hours after placement to have the result read.
The Mantoux method should be used for tuberculin skin testing; there is no role for multiple-puncture tests, such as the Tine test.1 The standard test material used in the Mantoux is intermediate-strength (5 tuberculin units) purified protein derivative (PPD). There are two commercially available PPD preparations in the United States, Aplisol and Tubersol; these have similar sensitivity and specificity in at-risk populations, but Tubersol is slightly more specific and therefore may be of benefit when testing low-risk populations (e.g., certain groups of health care workers who are required to undergo regular tuberculin testing).56 In addition, switching from Tubersol to Aplisol has been associated with false positive results.57
In reading a tuberculin skin test, the diameter of induration rather than of erythema should be determined and recorded. The criterion for a positive test (i.e., induration of ≥ 5 mm, ≥ 10 mm, or ≥ 15 mm) varies according to the population group to which the patient belongs, and the choice of criterion is influenced by the patient's likelihood of becoming infected with M. tuberculosis and the risk of developing active disease if infected28 [see Table 1]. Anergy testing along with tuberculin testing is not routinely recommended, especially in HIV-infected patients.1,28 In addition to its use as a diagnostic test for LTBI, a positive test may provide additional support for the diagnosis of active tuberculosis in culture-negative cases when there is a high clinical index of suspicion.
Table 1 Criteria for a Positive Tuberculin Skin Test by Risk Group97
All patients with a positive tuberculin skin test must be evaluated for evidence of active disease with a chest radiograph. In addition, sputum specimens should be tested if symptoms suggestive of tuberculosis are present or abnormalities are found on the chest radiograph.
Repeated tuberculin skin testing will not cause a truly tuberculin-negative person (i.e., one who has not been infected with M. tuberculosisor sensitized to other mycobacteria) to become tuberculin positive.58 In some persons with LTBI, the ability to react to tuberculin skin testing diminishes over time; administration of a tuberculin skin test to such persons can restore reactivity, thereby boosting the response to future tests.59 Boosting is believed to result from recall of waned, cell-mediated immunity; it is common in persons older than 55 years and in those born outside the United States who have been vaccinated with BCG. Two-step testing is done to avoid interpreting the boost as a recent conversion and new infection in persons who will be undergoing serial testing. If the reaction to the first tuberculin skin test is negative, the test is repeated in 1 to 3 weeks. Two-step testing should be performed when initially testing persons who have not had a test in the previous 12 months and who will be subject to regular testing in the future, such as health care workers and employees and residents of group settings.
NEW DIAGNOSTIC TESTS FOR LTBI
Because of the limitations of the tuberculin skin test, new diagnostic tests for latent tuberculosis infection are needed.55 A number of tests are under development. Two assays that utilize peripheral blood are commercially available: a whole-blood IFN-γ release assay (QuantiFERON-TB Gold [QFT-G], Cellestis Ltd, Victoria, Australia), which was approved by the Food and Drug Administration in 2005, and an enzyme-linked immunospot assay (T SPOT-TB, Oxford Immunotec, Oxford, England), which is approved in Europe.54,60,61,62 The QFT-G detects release of IFN-γ from lymphocytes of sensitized persons when their blood is incubated with two M. tuberculosis proteins called ESAT-6 and CFP-10, which are not found in BCG. According to Centers for Disease Control and Prevention guidelines, the QFT-G can be used in place of—not in addition to—the tuberculin skin test in all circumstances, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs (e.g., for health care workers).60 A positive QFT-G result should prompt the same evaluation as a positive tuberculin skin test (e.g., chest radiograph to exclude pulmonary tuberculosis and evaluation for treatment of LTBI). The QFT-G test is thought to be more specific than the tuberculin skin test. It is unclear whether the QFT-G test is as sensitive as the tuberculin skin test.
The advantages of T cell-based IFN-γ assays are that testing can be accomplished with a single patient visit, the test assesses responses to multiple antigens simultaneously, and the test does not boost anamnestic immune responses. Limitations of the currently available tests include the need to draw blood and to process the sample within 12 hours after collection.
It is hoped that the newer-generation tests that use M. tuberculosis-specific antigens will have improved utility, which should lead to wider availability and use of these tests.60 However, prospective studies are needed to determine whether IFN-γ responses are predictive of high risk of progression to active tuberculosis, to gauge the utility of such tests in specialized subgroups of patients (including children and HIV-infected persons) for whom there are currently few or no data on the use of these tests, and to ascertain whether treatment of LTBI on the basis of the results of IFN-γ responses will reduce the tuberculosis burden in low-incidence areas such as the United States.54
The keys to the diagnosis of tuberculosis are a high index of suspicion and familiarity with the range of clinical presentations, including atypical ones in HIV-infected patients that often reflect primary disease rather than reactivation of LTBI.63
Unfortunately, delay in diagnosis is common; such delays can increase the risk of a poor outcome and lead to further transmission of tuberculosis, including the precipitation of outbreaks in health care and institutional settings.6,64,65,66
Patients presenting with clinical manifestations suggestive of tuberculosis with pulmonary involvement should have a chest radiograph performed. In immunocompetent patients, the chest radiograph may show upper-lobe disease, often with cavitation [see Pulmonary Tuberculosis, above]. HIV-infected patients, especially those with advanced disease and low CD4+ T cell counts, are less likely to have cavitation visible on chest radiographs, regardless of the duration of symptoms. The longer the time since the onset of symptoms, the more likely it is that cavitation will be present. In HIV-infected patients, especially those with advanced disease who have a low CD4+ T cell count, there is a greater likelihood of atypical findings on chest x-ray that reflect primary disease; such findings may include lower-zone infiltrates or hilar or mediastinal adenopathy [see Tuberculosis in HIV-Infected Patients, above].
Although the findings on chest radiography may be suggestive of tuberculosis, definitive diagnosis requires identification of M. tuberculosisthrough culture. In addition, a positive culture for M. tuberculosis is a prerequisite for susceptibility testing.
A number of different diagnostic tests for tuberculosis are available. However, AFB smear and culture are critical in the evaluation of a patient with suspected tuberculosis.
Acid-Fast Bacteria Smear Microscopy
The Kinyoun and the Ziehl-Neelsen basic fuchsin stains are the traditional methods used for visualizing mycobacteria in clinical specimens. In the United States and other developed countries, an auramine-rhodamine stain with fluorescent microscopy is used because it is more sensitive and less time consuming than the carbol-fuschin stain (e.g., the Ziehl-Neelson stain). Throughout most of the world, AFB smear microscopy is the major diagnostic tool for tuberculosis. In the United States and other developed countries, AFB culture, which is more sensitive than an AFB smear, is also used in conjunction with smear microscopy. AFB smear microscopy has a sensitivity of only about 50% to 60% in culture-confirmed cases, in part because a positive smear requires a sputum sample containing 5,000 to 10,000 AFB/µl, whereas a positive AFB sputum culture requires only 10 to 100 AFB/µl.28 Another limitation is that smear microscopy cannot distinguish M. tuberculosisfrom other mycobacteria.
A presumptive diagnosis of tuberculosis can be made in the setting of a positive AFB smear and clinical manifestations consistent with the disease. Culture confirmation is necessary for a definitive diagnosis; NAA tests, which can be performed directly on clinical specimens, can also provide confirmation of M. tuberculosis on AFB smear-positive respiratory specimens.
A definitive diagnosis of tuberculosis generally depends on the isolation and identification of M. tuberculosis from a clinical specimen; most often this is a sputum sample from a patient with pulmonary disease. Conventional culture of mycobacteria with solid media requires incubation for 3 to 6 weeks. Use of broth-based media can result in recovery of a positive culture 10 to 14 days sooner than with solid media.67 Broth-based media are also preferable because they are more sensitive than solid media, although neither type of medium recovers all isolates.67,68 For these reasons, it is recommended that a broth system be used for primary mycobacterial culture but that a solid medium also be inoculated.
DNA probes can be used to rapidly identify colonies of M. tuberculosis complex (i.e., M. tuberculosis, M. bovis, M. africanum, and M. microti) and have replaced biochemical tests in most laboratories. Commercially available probes can identify the M. tuberculosis complex but do not differentiate M. tuberculosis from other members of the complex; they can also identify M. avium complex, M. kansasii, and M. gordonae. Probes provide species identification within a few hours with nearly 100% accuracy if sufficient growth is tested. However, a positive culture is required before the probe can be used for species identification. High-performance liquid chromatography can also be used to determine the mycobacterial species, but it is usually available only at large public health and reference laboratories.
Initial isolates from all patients should be tested for drug susceptibility to identify an effective antituberculous regimen.28 In addition, drug susceptibility tests should be repeated if the patient continues to produce culture-positive sputum after 3 months of adequate therapy or if the patient does not respond clinically to therapy. It has been proposed that susceptibility test results for the first-line antituberculous drugs be reported within an average of 28 days of receipt of the specimen in the laboratory; this requires the use of broth-based media for identification and susceptibility testing. According to the National Committee for Clinical Laboratory Standards Subcommittee for Antimycobacterial Susceptibility Testing, isolates of M. tuberculosis should be tested for susceptibility to isoniazid (at two concentrations), rifampin, ethambutol, and pyrazinamide (the latter three at one concentration each).69 Such testing provides comprehensive information regarding the initial four-drug therapy recommended for treatment of most tuberculosis patients in the United States.
If resistance to rifampin or to any two first-line drugs is found, the isolate should be tested for susceptibility to second-line drugs (e.g., capreomycin, ethionamide, kanamycin, ofloxacin, para-aminosalicylic acid, rifabutin, and streptomycin) and for susceptibility to ethambutol at a higher concentration than was used initially.69,70 Second-line drug testing can be done only on solid media, preferably using the agar proportion method. Results can take up to 2 months to become available.
Nucleic Acid Amplification Tests
NAA techniques can be used to identify mycobacterial DNA or RNA of M. tuberculosis in clinical specimens (e.g., sputum or other respiratory specimens) and provide immediate confirmation that a patient has tuberculosis. NAA testing has been most commonly used to confirm the diagnosis of tuberculosis in patients who have positive AFB smears on sputum or other respiratory specimens. Two commercially available tests are approved by the FDA for use on respiratory specimens.68,71 The tests are rapid, taking less than 6 hours, and are performed directly on clinical specimens. In sputum and respiratory specimens that are AFB smear-positive, NAA tests have sensitivities and specificities greater than 95%; in AFB smear-negative specimens, specificity remains above 95% but sensitivity is much lower, often less than 50%.24 The FDA has approved NAA tests in conjunction with cultures of respiratory specimens from patients who have not been treated for tuberculosis.71 NAA tests have been performed on nonrespiratory specimens, although they are not FDA approved for this use. The performance of NAA tests on nonrespiratory specimens has varied; the sensitivity appears to be less than that for respiratory specimens.68NAA tests are particularly useful when the positive predictive value of a positive AFB smear of sputum for M. tuberculosis is low. This is the case in settings where recovery of nontuberculous mycobacteria is common, such as with HIV-infected patients, especially those with advanced disease. Currently, NAA tests cannot replace conventional methods for the diagnosis and management of tuberculosis. In hospitalized patients, the AFB smear is used to assess infectivity and the need to institute isolation precautions against airborne infection. Culture must be performed to recover the isolate for susceptibility testing. Thus, NAA testing is a supplement to the traditional diagnostic tests, and it results in additional expense—predominantly, laboratory costs for reagents and technicians' time. The increase in laboratory expenditures, however, may be offset by savings elsewhere in the hospital or public health department. Hospitals can benefit from the ability to discharge patients from airborne-infection isolation rooms despite being AFB positive, when negative results on NAA testing show that they do not have tuberculosis. Negative NAA tests also can help avoid unnecessary therapy for tuberculosis and may shorten hospital stays. In public health departments, positive NAA test results can facilitate contact investigations of persons who have tuberculosis.
Additional Diagnostic Tests
Other diagnostic tests may be useful in facilitating the diagnosis of tuberculosis. Sputum induction by ultrasonic nebulization of hypertonic saline may be useful for patients who are not able to expectorate sputum. The yield of an induced sputum test appears to be as good as that of specimens obtained by fiberoptic bronchoscopy, and yield of repeated inductions may be superior.72,73 Bronchoscopy with bronchoalveolar lavage or biopsy is sometimes performed as a diagnostic test, especially when sputum cannot be obtained or in patients with radiographic abnormalities suggestive of other diagnoses (e.g., bronchogenic carcinoma). It is essential that specimens be submitted to the microbiology laboratory for AFB smear and culture to establish a diagnosis in such cases.
Molecular typing (so-called DNA fingerprinting) of M. tuberculosis isolates has proved very useful in furthering the understanding of the epidemiology of tuberculosis. Molecular typing has led to an increase in knowledge regarding the transmission dynamics of M. tuberculosis. It has also proved useful in the evaluation of patients with a second episode of tuberculosis, in that it enables one to differentiate relapses from reinfection with a new strain. Molecular typing is also helpful in evaluating outbreaks and in identifying laboratory cross contamination.8
To establish the diagnosis of extrapulmonary tuberculosis, appropriate specimens should be obtained for AFB staining, mycobacterial culture, and drug susceptibility testing.27,30 Depending on the clinical circumstances, specimens may include pleural fluid; pericardial or peritoneal fluid; pleural, pericardial, and peritoneal biopsy specimens; lymph node tissue; bone marrow; bone; blood; urine; brain tissue; or cerebrospinal fluid. Blood from patients with HIV infection should be sent for AFB culture when extrapulmonary or disseminated tuberculosis is suspected. Tissue specimens should also be examined microscopically, after routine and AFB staining, but the absence of AFB and of granulomas or even failure to culture M. tuberculosis does not necessarily exclude the diagnosis of tuberculosis. In some cases, a presumptive diagnosis of tuberculosis is made on the basis of epidemiologic findings (e.g., close contact of an active case), consistent clinical and radiologic findings, and a positive tuberculin skin test.
PRINCIPLES OF TUBERCULOSIS TREATMENT
The goals of antituberculosis therapy are to ensure a cure without relapse, to prevent death, to stop transmission of M. tuberculosis, and to prevent the emergence of drug-resistant disease.4 Therapy is initiated with a multidrug regimen to kill tubercle bacilli rapidly, to minimize or prevent the development of drug-resistant M. tuberculosis strains, and to eliminate persistent organisms from host tissue to prevent relapse. Active tuberculosis should never be treated with a single drug, because of the risk of emergence of resistance, and a single drug should never be added to a failing regimen.
The initial therapy for tuberculosis generally consists of a four-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol) [see Table 2]. Detailed discussion of the pharmacokinetics, pharmacodynamics, and available preparations of these drugs is beyond the scope of this chapter, but reviews of these subjects have been published.3,74
Table 2 Recommended Doses and Adverse Effects of Antituberculosis Medications for Adults*
Tuberculosis requires prolonged treatment. The minimum length of therapy for the treatment of drug-susceptible tuberculosis is 6 to 9 months with a rifampin-based regimen (so-called short-course therapy). Longer courses of therapy are required for drug-resistant tuberculosis, especially multidrug-resistant disease (i.e., disease caused by M. tuberculosis that is resistant to at least isoniazid and rifampin).Treatment of tuberculosis has two phases: initiation (also known as the bactericidal or intensive phase) and continuation (also known as the subsequent sterilizing phase). These phases reflect the current understanding of the pathophysiology of tuberculosis. Three separate subpopulations of M. tuberculosis are thought to exist in the host with tuberculosis.74 The first and largest of the subpopulations consists of rapidly growing extracellular organisms that mainly reside in well-oxygenated cavities (abscesses) containing 107 to 108organisms. The second subpopulation resides within poorly oxygenated, closed, solid, caseous lesions (e.g., noncaseating granulomas) containing 104 to 105 organisms. These organisms are considered semidormant and undergo only intermittent bursts of metabolic activity. The third subpopulation consists of a small number of organisms (fewer than 104 to 105) believed to be semidormant within acidic environments—both intracellular (e.g., in macrophages) or extracellular within areas of active inflammation and recent necrosis.
Initiation of tuberculosis treatment is usually with a four-drug regimen consisting of isoniazid (also called INH), rifampin, pyrazinamide (PZA), and ethambutol. Isoniazid and rifampin are the two most important antituberculous drugs and are the cornerstones of therapy. PZA is an important first-line drug that is a necessary component for so-called short-course therapy (i.e., 6 to 9 months). Of these agents, isoniazid is the most potent for killing the rapidly multiplying M. tuberculosis bacilli (i.e., those in the first subpopulation) during the initial part of therapy; that is, it has early bactericidal activity. Rifampin and ethambutol have less early bactericidal activity than isoniazid but considerably more than PZA, which has weak early bactericidal activity during the first 2 weeks of treatment. The use of drugs that have potent early bactericidal activity reduces the chance of the development of resistance.
The rapidly dividing population of bacilli (i.e., the first subpopulation) is eliminated early in effective therapy, and after 2 months of treatment, about 80% of patients are culture negative. The remaining (i.e., the second and third) subpopulations of M. tuberculosis account for treatment failures and relapses and are the reason that prolonged therapy is required for eradication. For the continuation phase of therapy, antituberculous drugs are chosen on the basis of their sterilizing activity, which is defined by a drug's ability to kill bacilli mainly in the second and third subpopulations. The use of drugs that have good sterilizing activity is essential for short-course therapy (e.g., 6-month regimens). Rifampin and PZA have the greatest sterilizing activity, followed by isoniazid and streptomycin. The sterilizing activity of rifampin persists throughout the course of therapy; however, the sterilizing activity of PZA is mainly seen during the initial 2 months of therapy.
Directly Observed Therapy
Successful treatment of tuberculosis depends not only on the correct choice of antimycobacterial drugs but also on the provision of those drugs within a clinical and social framework based on individual patient circumstances.3 Furthermore, the treatment of tuberculosis is much different from the treatment of other diseases because of the public health implications of the disease. Whether care is provided by a physician in private practice or through a public health program, the provider has the dual responsibility of selecting an appropriate regimen and ensuring that treatment is completed.3 For that reason, DOT is recommended for all patients with tuberculosis, in that it helps maximize completion rates [see Figure 6], decrease risk for emergence of resistance, and enhance tuberculosis control.75,76 DOT is generally provided by public health agencies.
Figure 6. Impact of directly observed therapy (DOT) on completion rates of therapy for pulmonary tuberculosis.74 Median completion rates were 61.4% for nonsupervised therapy, 78.6% for modified DOT (i.e., initial inpatient DOT followed by a variety of outpatient strategies, including self-administered medication), 86.3% for DOT, and 91.0% for enhanced DOT (i.e., DOT with multiple incentives and enablers).
INITIATION OF THERAPY
The decision to initiate combination antituberculosis chemotherapy (e.g., a four-drug regimen) should be based on epidemiologic information; clinical, pathologic, and radiographic findings; and the results of microscopic examination of AFB-stained sputum smears (or other diagnostic specimens, as appropriate) and cultures for mycobacteria.3 Given that M. tuberculosis is a relatively slow-growing organism and that cultures can take up to 4 to 5 weeks to become positive, empirical therapy with an appropriate multidrug regimen needs to be initiated when there is high clinical suspicion of active disease. Therapy should be started before culture confirmation and in some cases before AFB smear microscopy results are known. NAA tests [see Nucleic Acid Amplification Tests, above] may be useful in selected cases, because of their ability to provide an immediate definitive diagnosis (e.g., confirmation of AFB smear-positive respiratory specimens). The threshold for initiating empirical therapy should be low for patients with potentially life-threatening forms of tuberculosis that can progress rapidly, such as tuberculous meningitis, pericarditis, or miliary disease.
Guidelines published by the American Thoracic Society (ATS), the CDC, and the Infectious Diseases Society of America (IDSA) outline recommended treatment regimens for use in the United States and other industrialized countries [see Table 3]. Recommendations are graded and evidence based, using the IDSA-United States Public Health Service rating system.
Table 3 Treatment Guidelines for Drug-Susceptible Pulmonary Tuberculosis in Adults*3
Drug-Susceptible Pulmonary Disease
When testing confirms drug susceptibility in patients who have been started on an empirical four-drug regimen (e.g., isoniazid, rifampin, PZA, and ethambutol) for pulmonary disease, treatment can be modified accordingly [see Table 3] [see Figure 7]. PZA can be discontinued after 2 months of therapy (i.e., at the end of the initiation phase). Ethambutol can also be discontinued after 2 months of therapy or as soon as drug susceptibility is confirmed. Isoniazid and rifampin are maintained in the continuation phase (4 more months) for a minimum of 6 months of therapy. Patients at high risk for relapse include those with cavitary pulmonary tuberculosis who remain culture positive after 2 months of therapy.77 Such patients should have the continuation phase of therapy extended 3 additional months (to 7 months in the continuation phase and a total of 9 months of therapy).
Figure 7. Treatment of drug-susceptible pulmonary tuberculosis.54 When tuberculosis is proven or strongly suspected, isoniazid, rifampin, pyrazinamide, and ethambutol should be used for the 2-month initiation phase of treatment. Ethambutol may be discontinued if drug susceptibility testing indicates no drug resistance; pyrazinamide may be discontinued after 2 months. After 2 months of treatment, an acid-fast bacteria (AFB) smear and tuberculosis culture of sputum are performed. The duration of treatment for the continuation phase depends on the presence or absence of cavitation on the initial chest radiograph, the results of testing at 2 months, and the HIV status of the patient. In HIV-negative patients with no cavitation on the initial chest radiograph and negative AFB smears after 2 months, the continuation phase may consist of either once-weekly isoniazid and rifapentine or isoniazid and rifampin daily or twice weekly for a total of 6 months of treatment. In patients who received isoniazid and rifapentine and in whom 2-month cultures are positive, treatment should be extended 3 months, for a total of 9 months of treatment. HIV-infected patients with CD4+ T cell counts below 100/µl should receive isoniazid and rifampin daily or three times weekly for the continuation phase. Rifapentine should not be used in HIV-positive patients or in any patients with extrapulmonary tuberculosis.
In addition to the total duration of therapy, the number of completed doses is important for treatment success. Doses should be counted and tracked to ensure the proper amount of therapy is delivered. Lack of adherence to antituberculosis therapy is the most common cause of treatment failure, relapse, and the emergence of drug resistance. DOT has been proved to improve completion rates and outcome, and it should be considered the standard of care [see Figure 6].3 Drug-susceptible disease can be successfully treated with antituberculosis therapy administered on an intermittent basis (e.g., twice or thrice weekly), especially in the continuation phase; this tactic facilitates supervision of therapy, thereby helping to improve outcomes. Intermittent therapy (e.g., therapy administered twice or thrice weekly) should be given by DOT only and only to patients with drug-susceptible disease [see Table 3].
Because tuberculosis may be the disease that brings an HIV-infected person into the health care system for the first time, all patients diagnosed with tuberculosis should be offered—and strongly encouraged to undergo—HIV serologic testing.3 The treatment of tuberculosis in patients with HIV coinfection is similar to that in HIV-seronegative patients, with two exceptions. First, HIV-infected patients should not be treated with once-weekly isoniazid-rifapentine in the continuation phase; this regimen is reserved for highly selected HIV-seronegative patients without cavitary disease. In HIV-infected patients, the risk of relapse with this regimen is increased to an unacceptable degree; when relapse occurs, it is often with organisms that have acquired rifamycin resistance.78 Second, HIV-infected patients with CD4+ T cell counts of less than 100/µl should not receive twice-weekly intermittent regimens (e.g., isoniazid-rifampin or isoniazid-rifabutin), because acquired rifamycin resistance has also been reported in this setting.3,79 Instead, HIV-infected patients with low CD4+ T cell counts should receive daily or thrice-weekly therapy.3 HIV-infected patients with drug-susceptible pulmonary tuberculosis can generally be treated for 6 months [see Table 3]. For HIV-infected patients with tuberculosis who are slow to respond to therapy or who have a suboptimal response (e.g., whose cultures are positive after 2 months of therapy), prolongation of the continuation phase to 7 months (for a total of 9 months of treatment) is suggested.3
In the United States, most patients with HIV-related tuberculosis have advanced immunosuppression and high plasma HIV RNA levels at the time of diagnosis.80 Thus, they meet the criteria for antiretroviral therapy.81 In addition, the use of antiretroviral therapy during the treatment of tuberculosis in persons with HIV infection may improve tuberculosis treatment outcomes.3,82 However, strict adherence to antiretroviral therapy is necessary to promote a sustained virologic response; moreover, the use of antiretroviral therapy in HIV-infected patients with tuberculosis is complicated by overlapping toxicity profiles of some antituberculosis and antiretroviral drugs, as well as by complex drug-drug interactions and the occurrence of paradoxical or immune reconstitution reactions.
Paradoxical or immune reconstitution reactions are characterized by exacerbation of symptoms and signs or by radiographic manifestations of tuberculosis. These reactions are more common in HIV-infected patients who are started on antiretroviral therapy early in the course of antituberculosis therapy.83 Therefore, although there are no data to indicate the best time to start antiretroviral therapy, some experts have recommended delaying its initiation, if possible, until after the patient has received 1 to 2 months of antituberculosis therapy.3
The use of antiretroviral therapy during tuberculosis treatment is complex for both the patient and the physician. Thus, there needs to be close coordination of care between the physicians treating each disease. The interaction between rifampin (and other rifamycins) and antiretroviral agents, especially the protease inhibitors, is a major concern and a challenge in treating tuberculosis in HIV-infected patients. Because rifamycins induce the hepatic cytochrome P-450 3A enzyme system, their use leads to reductions in the serum levels of a variety of drugs—in some cases to nontherapeutic ranges. A long list of clinically significant drug-drug interactions involving the rifamycins have been reported, including those with protease inhibitors and nonnucleoside reverse transcriptase inhibitors; there are generally no significant drug-drug interactions with nucleoside reverse transcriptase inhibitors (NRTIs) [see 7:XXXIII HIV and AIDS]. Rifampin is the most potent cytochrome P-450 inducer, followed by rifapentine and rifabutin. Conversely, the protease inhibitors are cytochrome P-450 inhibitors that raise rifabutin levels to potentially toxic concentrations and necessitate dose modifications. Rifampin cannot be given with most protease inhibitors, because its use results in low serum levels of these drugs. Rifabutin lowers drug serum levels to a lesser degree than rifampin, and therefore it can be used with certain protease inhibitors.
Possible options in the treatment of tuberculosis in HIV-infected patients include the following: (1) use of a rifampin-based regimen, which can be given to patients receiving antiretroviral therapy with NRTIs and efavirenz; (2) the substitution of rifabutin for rifampin in a multidrug regimen when the patient is receiving antiretroviral therapy with a protease inhibitor; (3) the use of rifampin in a multidrug regimen when antiretroviral therapy cannot be given; and (4) the use of a non-rifamcyin-based regimen in patients receiving antiretroviral drugs, including protease inhibitors. Despite the potential for avoiding drug-drug interactions, however, regimens that do not include a rifamycin are not recommended for patients with HIV infection, because worse outcomes have been reported.80
It must be emphasized that recommendations on the use of antiretroviral therapies in HIV-infected patients with tuberculosis continue to evolve. The latest recommendations and information, including acceptable antiretroviral regimens and necessary dose adjustments, are available from CDC on the Internet (http://www.cdc.gov/nchstp/tb/TB_HIV_Drugs/TOC.htm).84
The basic principles that underlie the treatment of pulmonary tuberculosis also apply to extrapulmonary forms of the disease. A 6-month course of therapy is recommended for treating tuberculosis involving any site except the meninges; for the meninges, a 9- to 12-month regimen is recommended. Prolongation of therapy also should be considered for patients with tuberculosis that is slow to respond, regardless of the site.
The addition of corticosteroids is recommended for patients with tuberculous pericarditis and meningitis, because it improves outcome and decreases mortality.3,85,86 Evidence-based guidelines for the treatment of extrapulmonary tuberculosis and the adjunctive use of corticosteroids have been developed [see Table 4]. Corticosteroids should be given for tuberculous pericarditis during the first 11 weeks of antituberculosis therapy. Corticosteroids do not reduce the risk of the development of constrictive pericarditis, however. For patients with tuberculous meningitis, adjunctive dexamethasone is recommended.
Table 4 Evidence-Based Guidelines for Duration of Therapy for Drug-Susceptible Extrapulmonary Tuberculosis and Adjunctive Use of Corticosteroids*3,85
Tuberculosis in Pregnant Patients
Tuberculosis that is discovered during pregnancy should be treated without delay. Because tuberculosis can spread to the fetus, treatment in pregnant women should be initiated whenever the probability of maternal disease is moderate to high.
The initial treatment regimen in pregnant patients consists of isoniazid, rifampin, and ethambutol. Consideration should be given to including PZA in the initial regimen as well: PZA has not been widely used in the United States to treat pregnant women with tuberculosis, but it is recommended for use in this setting by the WHO and the International Union Against Tuberculosis and Lung Disease, as well as some public health agencies in the United States.3,87 PZA is recommended for use in all HIV-infected pregnant patients and in pregnant patients who are thought to be at high risk for drug-resistant tuberculosis (pending susceptibility test results). If PZA is not included in the regimen, the minimum duration of treatment is 9 months. Supplemental pyridoxine (vitamin B6), 25 to 50 mg a day, is indicated for all pregnant women taking isoniazid, to prevent peripheral neuropathy. Aminoglycosides and fluoroquinolones should be avoided in pregnancy because of potential adverse effects on the fetus.
Treatment of drug-resistant tuberculosis, especially MDR-TB, is quite challenging and should be done by, or in close consultation with, an expert in this subject. Recommendations for the treatment of drug-resistant tuberculosis have been developed [see Table 5]. Treatment of isolated isoniazid resistance can be accomplished with a 6-month regimen of daily rifampin, PZA, and ethambutol. Treatment of isolated rifampin resistance requires a minimum of 12 months of therapy with a regimen such as isoniazid, PZA, ethambutol, and a fluoroquinolone. Treatment of MDR-TB (resistance to both isoniazid and rifampin) requires 18 to 24 months, depending on the full resistance pattern, and is associated with significantly higher morbidity and mortality than drug-susceptible disease. Treatment of MDR-TB requires the use of second-line drugs, which have less in vitro activity and significantly more toxicity than first-line drugs [see Table 2].
Table 5 Potential Regimens for the Treatment of Drug-Resistant Tuberculosis3
Common errors that lead to the emergence of drug resistance include the addition of a single drug to a failing regimen, failure to identify preexisting or acquired drug resistance, initiation of an inadequate primary regimen, failure to identify and address noncompliance, and use of monotherapy for active disease (in cases in which therapy for latent tuberculosis was prescribed but active disease was present).88 In patients suspected of having MDR-TB (e.g., those who failed to complete an earlier regimen or who followed their therapy erratically, those with recent exposure to an MDR-TB case, or those from extremely high-risk areas), the physician should consider initiating therapy with extended empirical regimens, pending culture results. This is especially the case for patients with extensive pulmonary disease or extrapulmonary disease such as tuberculous meningitis or miliary disease. Documented MDR-TB requires treatment with at least four drugs (and more if possible) to which the organisms are susceptible, such as three oral drugs and one injectable agent [see Table 5].
The role of surgery in MDR-TB has not been examined in randomized studies but is thought by some experts to be beneficial in selected cases. In one case series, surgical resection in conjunction with fluoroquinolone therapy was associated with improved microbiologic and clinical outcomes in 205 patients with MDR-TB.89 Surgery should be deferred until the patient has completed several months of intensive chemotherapy, and it should be performed by an experienced surgeon.3
MONITORING RESPONSE TO TREATMENT
For patients undergoing treatment of pulmonary tuberculosis, a sputum specimen for AFB smear and culture should be obtained at least monthly until two consecutive specimens are culture negative.3 It is essential to obtain an AFB sputum smear and culture after 2 months of therapy, because of their value in predicting risk of relapse. Drug susceptibility tests should be repeated on M. tuberculosis isolates from patients whose cultures are positive after 3 months of treatment.
In patients with pulmonary tuberculosis, a repeat chest radiograph should be taken after 2 months of therapy; more frequent chest radiographs are not indicated. However, a chest radiograph taken at the completion of therapy can be useful for providing a baseline against which subsequent films can be compared.
Bacteriologic monitoring is more difficult in patients with extrapulmonary disease. In these cases, the response to treatment often must be assessed clinically because it is not feasible to obtain follow-up cultures.
All patients undergoing treatment of tuberculosis should be seen on a monthly basis; at each visit, they should undergo a clinical evaluation to identify possible adverse effects of the antituberculosis medications and to assess adherence. Baseline liver function tests, creatinine level, and platelet count should be obtained on all patients. In patients taking first-line antituberculosis drugs, ATS/CDC/IDSA guidelines do not recommend monthly liver or renal function tests during treatment unless baseline abnormalities were present or there are clinical reasons to obtain the tests.3 Patients taking ethambutol should be questioned monthly regarding visual disturbances; monthly testing of visual acuity and color vision is recommended for those treated with dosages higher than 20 mg/kg/day or for those who require ethambutol for more than 2 months.
CONTACT INVESTIGATION AND REPORTING OF TUBERCULOSIS CASES
Physicians are required by law to report tuberculosis cases to their local public health agency. In some hospitals, this is handled by the infection control department, but the physician should ensure that the case has been reported expeditiously, so that the local health department can contact the patient while he or she is still hospitalized. This will help to ensure that the patient is not lost to follow-up after discharge. Discharge planning should be carried out in a collaborative fashion with the involvement of the public health department, which should have the resources and the ability to provide DOT to patients with tuberculosis in the outpatient setting. The local public health agency is responsible for conducting a contact investigation to identify others who have been exposed to an infectious patient (e.g., in the home, at work, and in other social settings). This can lead to the identification of newly infected contacts, for whom treatment of latent tuberculosis is a priority, and it can lead to other potential cases. In addition, when the patient is a child, the contact investigation can lead to the identification of the source case. Priority for contact investigations should be given to instances in which infants or HIV-infected persons (or other highly immunocompromised persons) have been exposed, given the rapid progression from infection to active disease in these settings.
Therapy for latent tuberculosis can markedly reduce the risk of progression to active disease and is recommended for patients who are at increased risk for disease progression. Patients with LTBI (i.e., those who test positive on tuberculin skin testing or other diagnostic tests but whose chest radiograph is negative and who have no signs or symptoms of tuberculosis) who are at increased risk for progression to active disease should be encouraged to undergo therapy.
The CDC and ATS have issued guidelines on the treatment of latent tuberculosis [see Table 6]. The preferred regimen is a 9-month course of isoniazid; 6 months of isoniazid is an alternative in HIV-seronegative adults. The recommendation for this duration of therapy comes from reanalysis of data from older trials.90 Rifampin taken for 4 months is an alternative for the treatment of LTBI and is recommended for adults suspected of harboring an isoniazid-resistant strain of M. tuberculosis.
Table 6 CDC Guidelines for the Treatment of Latent Tuberculosis in Adults97
A 2-month regimen of rifampin plus PZA for the treatment of LTBI is not recommended, because of its unacceptably high rate of hepatotoxicity in these patients. A CDC survey suggests that the risk of death with this regimen is nearly 1 in 1,000 persons, and the rate of hospitalization for drug-induced hepatotoxicity is 3 in 1,000 persons.91 Rifampin and PZA, however, remain an important component of a multidrug regimen for patients with active tuberculosis. In LTBI, isoniazid may also be given twice weekly by DOT to facilitate adherence in institutional settings or when resources are available.
Patients receiving therapy for LTBI should have an initial clinical evaluation, followed by follow-up evaluations at least monthly; no more than 1 month's supply of medication should be dispensed at a time. The monthly clinical evaluation should include questioning about side effects and a brief clinical assessment for signs of hepatitis. Although adverse reactions to isoniazid are not common, they can be serious. Hepatotoxicity is the most important side effect. However, at a tuberculosis clinic in Seattle, hepatotoxicity occurred in only 0.15% of patients who completed isoniazid monotherapy for LTBI—a rate much lower than those reported in earlier studies.92 The rate of isoniazid-related hepatotoxicity has been estimated to be 1 to 3 per 1,000 patients. Age is a risk factor: isoniazid-induced hepatotoxicity is rare in patients younger than 20 years, but the rate increases with advancing age. Risk may also be higher in patients with underlying liver disease (including hepatitis C), in those with a history of heavy alcohol consumption, and in the postpartum period (especially for Hispanic women). Asymptomatic, and generally transient, elevations of the aminotransferase level can occur in 10% to 20% of patients taking isoniazid for LTBI. The risk of fatal hepatitis from isoniazid is currently reported to range from 0 to 0.3 (median, 0.04) per 1,000 patients.91,92 Death has been associated with continued administration of isoniazid despite onset of hepatitis symptoms. The drug should be discontinued when levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) exceed five times normal in asymptomatic patients or three times normal in those with symptoms.
Patients should be advised to discontinue isoniazid at the onset of symptoms that are consistent with hepatitis (e.g., nausea, loss of appetite, and dull midabdominal pain) and to immediately seek medical evaluation should these symptoms occur. Liver function tests should be obtained for any patient who develops symptoms suggestive of hepatitis. We recommend baseline liver function tests for all adult patients at the start of therapy for LTBI. However, ATS/CDC guidelines recommend baseline laboratory testing only for patients whose initial evaluation suggests a liver disorder and for those at increased risk for hepatotoxicity, including HIV-infected patients, pregnant women, women in the immediate postpartum period (i.e., within 3 months after delivery), patients with a history of chronic liver disease (e.g., hepatitis B, hepatitis C, alcoholic hepatitis, or cirrhosis), regular users of alcohol, and patients at risk for chronic liver disease.1 Baseline laboratory tests should also be obtained in patients who are taking other potentially hepatotoxic medications for chronic medical conditions. Active hepatitis and end-stage liver disease are relative contraindications to the use of isoniazid for treatment of latent tuberculosis. Routine laboratory monitoring (e.g., monthly AST or ALT measurement) during treatment of latent tuberculosis is recommended for persons whose baseline liver function test results are abnormal and for other patients at risk for hepatic disease (see above).
Peripheral neuropathy is also a side effect of isoniazid. It is relatively uncommon, but the risk is increased in persons with a nutritional deficiency, as well as those with diabetes mellitus, HIV infection, renal failure, or alcoholism, and in women who are pregnant or breast-feeding. Pyridoxine (25 to 50 mg a day) is recommended for patients with these risk factors to help prevent neuropathy. Some clinicians routinely give supplemental pyridoxine to all patients taking isoniazid.
BCG vaccination involves use of a live attenuated strain of M. bovis. The primary benefit of BCG administration appears to be in preventing disseminated tuberculosis and tuberculous meningitis in young children; variable efficacy has been reported in adults. BCG has had little effect on the global epidemiology of tuberculosis. BCG is not recommended for use in the United States but is widely used outside of the United States, especially in developing countries. Interestingly, in the tropics, administration of BCG has been associated with a decreased risk of leprosy.93 The vaccine can produce a positive tuberculin test in recipients, and because of the low incidence of new tuberculous infections in the United States, case finding and treatment of latent tuberculous infection are considered more efficient and effective strategies. Interpretation of a tuberculin skin test reaction is not changed for patients who have received BCG,1 because tuberculin sensitivity tends to wane considerably after BCG vaccination, and BCG is often given in areas where tuberculosis is endemic. Given that many BCG-vaccinated persons come from areas with a high prevalence of tuberculosis, it is important that those who have significant reactions to the tuberculin skin test be evaluated for the presence of disease and managed accordingly. Appropriate follow-up includes a careful medical history, a chest x-ray to rule out disease, and evaluation for treatment of latent tuberculosis. Newer diagnostic tests are needed for distinguishing between infection with M. tuberculosis and immunization with BCG.
Tuberculosis infection control efforts, utilizing a hierarchy of measures recommended by the CDC, have proved effective in preventing nosocomial transmission of tuberculosis.22,93,94 Atop this hierarchy are administrative controls, which include high suspicion for tuberculosis, careful screening of patients, precautions against airborne infection for patients suspected of having tuberculosis, and prompt diagnosis and initiation of effective therapy. Engineering controls and respiratory protection constitute the second and third tiers of the hierarchy of control measures. Guidelines for implementing a tuberculosis infection control program in health care facilities have been published.95
Editors: Dale, David C.; Federman, Daniel D.