Chapter 133 Tuberculosis

Transcription

1 Chapter 133 Tuberculosis Peter E. Sokolove and Robert W. Derlet PERSPECTIVE History and Epidemiology Tuberculosis (TB) has plagued humankind throughout recorded history. Clear evidence of tuberculous lesions of bone has been found in Egyptian mummified human remains that date to 3400 BCE. 1 The presence of TB also has been microscopically confirmed in the mummies of small children, one from the dynastic period of Egyptian history and one from pre-columbian southern Peru around 700 CE. 1-3 Hippocrates (460 to 370 BCE) is credited for providing the first accurate clinical description of TB. He coined the term phthisis ( a melting or wasting away ) to describe the wasting character of the disease, which he noted also was associated with fever and incurable lung ulcerations. 4 TB became a major public health problem during the Industrial Revolution. The corresponding urbanization of European cities led to overcrowding, widespread poverty, and poor hygienic conditions that were ideal for the epidemic spread of the disease throughout western Europe from the early 1600s through the 1800s. 5 Approximately 25% of all adult deaths in Europe were caused by TB during this period, and in 1861 Oliver Wendell Holmes named it the white plague. 1 TB gradually became a global epidemic as Europeans colonized North America and explored and colonized other parts of the world. 5,6 The TB epidemic peaked in western Europe in the early 1800s and by 1900 had peaked in the Americas. Globally, the disease still has not reached a peak in some developing countries in Africa and Asia. 7 Laënnec, who invented the stethoscope in 1816, accurately described the evolution of TB, from the small initial tubercle through all of its pathologic manifestations, in Twenty years later, Schönlein also recognized the tubercle as the fundamental anatomic lesion and named the disease tuberculosis. 8 Koch identified the tubercle bacillus in 1882, and Roentgen s discovery of x-rays in 1895 greatly improved the ability to diagnose TB early in the disease course. 1,4 In 1892, Biggs instituted a comprehensive program of TB control in New York City that included public education, systemic surveillance, isolation of patients, nursing follow-up, improved sanitation, and free sputum testing. 8,9 These types of programs and the subsequent introduction of the antituberculosis drugs led to an impressive decline in the incidence of TB throughout the 20th century. Between 1953 and 1985, TB cases decreased by an average of 5.8% per year. 10 As recently as the 1970s, U.S. health officials believed that TB was well under control and could soon be eradicated. 11 Unfortunately, as the incidence and perceived importance of the disease decreased, so did the public health programs to control it. 12 The premature decline in government for TB control programs made it impossible to manage the disease appropriately. The decline of the infrastructure dedicated to TB control during the late 1980s and early 1990s was compounded by new problems including the human immunodeficiency virus (HIV) acquired immunodeficiency syndrome (AIDS) epidemic, increasing immigration from countries with high TB prevalence, increasing occurrence of TB in institutional living settings, escalating poverty, substance abuse, homelessness, and urban overcrowding. These factors contributed to a resurgence of TB in the United States from 1986 through 1992 and to the emergence of drug-resistant strains of Mycobacterium tuberculosis (MTB). 12 Worldwide, the disease had become so widespread that in 1993 the World Health Organization declared TB a global emergency. TB is currently the world s second leading infectious cause of death, and one third of the world s population has been infected by TB. 13 Each year more than 8 million people acquire active TB infection and nearly 2 million die from the disease. 14 Elderly persons who harbor dormant infection that is reactivated constitute an important reservoir of MTB in the United States. 15 Debilitating disease or immunosenescence may predispose the affected person to reactivation. Nursing homes are particularly vulnerable to TB outbreaks because reactivation of disease in remotely infected persons may be followed by epidemic spread among the many susceptible hosts living in close quarters. Immigration from endemic countries is another major factor. 6,13 As reported in 2002, a majority of U.S. TB cases occur among foreign-born persons. 16 The largest numbers of people with TB originate from Mexico, the Philippines, Vietnam, India, and China, accounting for more than one half of all TB cases among foreign-born persons. 17 Homelessness also has contributed to the spread of TB in major urban centers. Homelessness often is associated with conditions that decrease resistance to TB, such as malnutrition, alcoholism, or substance abuse. MTB infection in the homeless population may quickly progress to active TB infection. 18 The HIV/AIDS epidemic has had the greatest impact on the reemergence of TB in the United States. 19 The pandemic of HIV-related TB has led to an increase in TB cases among non HIV-infected people owing to the higher numbers of 1793

2 PART III Medicine and Surgery / Section Twelve Infectious Diseases 1794 source cases in the community. 20 The rate of TB among patients who are HIV-infected and TB skin test positive is approximately 200 to 800 times higher than that estimated for the U.S. population overall. 21 The reemergence of TB also has affected children. Between 1962 and the mid-1980s, the rates of childhood TB in the United States decreased an average of 6% a year. 22,23 This trend has reversed along with the young urban adult trend, and the number of cases reported in children 4 years of age or younger increased 36% from 1985 through This increase reflected ongoing transmission of TB in the community, because TB in young children must result from recent infection. 10 After a 32-year decline, the number of TB cases in the United States increased 20% between 1986 and By 1992, roughly 14% more cases (26,673) were reported over the 1985 nadir. This trend, however, reversed in 1993, largely owing to the mobilization of new federal resources provided to the states for TB control and prevention. 12 The number of reported cases during 1996 decreased in each age group, as well as in all ethnic groups. 24 The number of reported cases in the United States during 2006 (13,767) represents a 48% decrease from 1992 and reflects the 14th consecutive year of decline. 17 Although the rapid resurgence of TB appears to be subsiding in the United States, there is no justification for complacency. Rates of newly diagnosed TB are still significant in different regions of the country and among certain demographic groups. 17 The populations most likely to acquire and transmit TB infection commonly are seen by emergency physicians, who then necessarily play a key role in identification, prevention, and treatment. Etiology One microorganism, M. tuberculosis, causes human TB in nearly all cases. Humans constitute the sole known reservoir for MTB. Two other pathogenic mycobacteria, Mycobacterium bovis and Mycobacterium africanum, have on rare occasions been implicated as causing TB. M. bovis is transmitted by drinking milk from diseased cows, but because pasteurization of milk is now common, it has become a relatively unusual cause of TB. M. africanum also is a rare cause of human TB. This mycobacterium is thought to be intermediate in pathogenicity between M. tuberculosis and M. bovis and has been documented to cause human TB, predominantly in Africa. 25 Worldwide, MTB remains the major causative agent. MTB is an intracellular, aerobic, nonmotile, non sporeforming bacillus with a waxy lipid coat. 25 This coating makes MTB resistant to decolorization with acid alcohol after staining hence the term acid-fast bacillus (AFB). MTB grows slowly: Its generation time is 15 to 20 hours, compared with less than 1 hour for some common bacteria; cultures take 4 to 6 weeks to grow on standard solid media. 25 MTB produces neither endotoxins nor exotoxins. Its cell components are immunoreactive; some are immunosuppressive, and others are the agents of granuloma formation, macrophage activation, host toxicity, and modification of the immune response. 26 PRINCIPLES OF DISEASE Transmission TB is transmitted primarily by the respiratory route; transmission by other routes, such as direct inoculation, occurs primarily among health care workers. Patients with active disease expel MTB in liquid droplets during coughing, sneezing, and vocalizing. A single cough or 5 minutes of talking can produce 3000 infectious droplets, and sneezing can produce an even higher number. 6 The droplets rapidly evaporate, and the desiccated bacilli circulate air-borne for prolonged periods. These infective particles, or droplet nuclei, measure 1 to 5 µm in diameter, contain one to three tubercle bacilli, and when inhaled can travel to the distal alveoli. The susceptible host may become infected when only a few of the droplet nuclei are inhaled. Fomites are not important in the transmission of the disease, and patients rooms, eating utensils, and bed clothes do not require special decontamination procedures. 25 Because the infectious droplet nuclei are airborne, exchanging contaminated air is the most important environmental control. In addition, MTB is susceptible to ultraviolet radiation, and transmission rarely occurs outdoors because of the dilution of infectious particles and exposure to ultraviolet radiation. 27 The risk for TB transmission increases when source patients have airway and cavitary disease. Infectivity correlates with the number of organisms seen on sputum smear, the extent of pulmonary disease, and the frequency of cough. After institution of proper chemotherapy (with regimens comprising three or four drugs) for 2 weeks, patients with initially AFB-negative sputum smears can be considered noncontagious. However, after 2 weeks of treatment, patients who initially were smear-positive may still have viable MTB detectable in their post-treatment sputum cultures, and patients with extensive disease may still have AFB detectable on their post-treatment sputum smears. The latter two groups generally should still be considered contagious. 28 There is currently no clear epidemiologic evidence to define better the contagiousness of patients after they are started with effective therapy. 28 The Centers for Disease Control and Prevention (CDC) has published guidelines requiring presence of three negative smears on different days as the criterion for removing a patient from respiratory isolation, but debate is ongoing regarding this recommendation. 29,30 Extrapulmonary TB also may be infectious but only if in the oral cavity or an open skin lesion. 29 Transmission of MTB to health care workers caring for patients with skin ulcers and draining tuberculous abscesses has been reported. 31 Irrigation of the abscess may aerosolize the bacilli, forming infectious droplet nuclei. 32 Pathogenesis When infectious droplet nuclei are inhaled, the airflow through the bronchial tree tends to deposit them in the midlung zone on the respiratory surface of the alveoli. 25 The deposition launches a complex series of immunologic events. Dannenberg has organized the complex pathogenesis of TB into four stages. 33 Stage 1 The first stage begins when an alveolar macrophage phagocytoses the recently inhaled bacillus. A macrophage from a resistant host can immediately destroy a less virulent bacillus. In these cases, no tuberculous infection develops and the process ends. If a virulent bacillus can overcome a macrophage s microbicidal capability, the infection may progress to the next stage. Stage 2 When the alveolar macrophage is unable to destroy the inhaled tubercle bacilli, the bacilli replicate until the macrophage

3 lyses. Circulating monocytes are attracted to the site of infection by the released bacilli, cellular debris, and various chemotactic factors. The monocytes differentiate into macrophages and ingest the free bacilli. Initially, these new macrophages are not activated and cannot destroy or inhibit the mycobacteria. The bacilli multiply logarithmically within macrophages and accumulate at the primary focus of infection, now called a tubercle. 34 The infected macrophages also may be transported through lymphatics to regional lymph nodes, from which they can reach the bloodstream, with subsequent spread. During this lymphohematogenous dissemination, the pathogens tend to distribute preferentially to lymph nodes, kidney, epiphyses of long bones, vertebral bodies, meningeal areas, and the apical posterior areas of the lungs. 25 These sites may be favored because of a high oxygen tension. Some investigators, however, believe that the lung apices are favored because of impaired clearance mechanisms from poor lymph flow. 25 Stage 3 The third stage of TB begins 2 to 3 weeks after the initial infection, with development of the immune response that terminates the unimpeded growth of MTB. 33 Cell-mediated immunity occurs through CD4 + helper T cells. 35 When the T cell encounters mycobacterial antigens, it is activated and produces an expanded population of specific T cells. These T cells secrete cytokines (e.g., interferon-γ [IFN-γ], tumor necrosis factor) that attract and activate monocyte-macrophages. Once activated, the macrophages, containing previously ingested mycobacteria and their progeny, kill the bacilli. The destruction of the mycobacteria is associated with the formation of epithelioid cell granulomas and clearance of the organisms. 34 Delayed-type hypersensitivity is mediated by cytotoxic CD8 + suppressor T cells. 35 The cytotoxic cells kill nonactivated macrophages laden with mycobacteria and thus cause local tissue destruction as well. Delayed-type hypersensitivity results in the formation of caseating necrotic granulomas. This stops bacillary growth; mycobacteria, now extracellular, cannot multiply in this acidic, anoxic, extracellular environment. 34 Tubercle bacilli can survive dormant in this solid caseous material for years. 34 The host s resistance determines whether the disease remains dormant or immediately progresses to active disease. In the immunocompetent host with strong cell-mediated immunity, the primary lesion is effectively walled off by epithelioid cells. Eventually, the caseous center inspissates, and the disease is arrested, often for a lifetime. 33 Similarly, at sites of lymphohematogenous spread, the mycobacteria are quickly destroyed, with little caseous necrosis, by a rapid immunologic response. 33 The rapid destruction of the mycobacteria by cellmediated immunity terminates the infectious process, and the only evidence of the infection is conversion to a positive tuberculin (purified protein derivative [PPD]) skin test result. 25 This sequence of events from stage 1 to stage 3 represents the pathogenesis of primary TB in the immunocompetent patient. 35 In most cases, primary TB is subclinical and selflimited. In the immunocompromised host, however, clinically active primary disease may develop rapidly after the initial MTB infection. The less-resistant host with weak cell-mediated immunity relies more on delayed-type hypersensitivity to control the infection. The primary lesion is surrounded by nonactivated macrophages so it is not effectively walled off, and the caseous center expands, compromising more lung tissue. If the infection eventually can be contained by the host, any initial mani festations may go unnoticed, and the infection may be evident only radiographically as healed parenchymal calcifications of the primary or Ghon focus and of the regional lymph nodes. 25 If host defenses are unable to contain the primary infection, however, as can occur in infants and immunosuppressed adults, the primary focus may become an area of advancing pneumonia. 25 This process is called primary progressive TB. In addition, this host may be unable to control the infection at the sites of lymphohematogenous spread, resulting in formation of multiple uncontrolled caseous tubercles and development of disseminated TB. 34 HIV-infected patients are particularly susceptible to primary progressive TB because HIV specifically targets CD4 + cells and macrophages. Stage 4 The final stage usually occurs months to decades after an apparent recovery from the initial infection. TB may progress to stage 4 even in immunocompetent persons. Usually, host factors lead to decreased resistance and reactivation of dormant foci of MTB. The progression is due to liquefaction and cavity formation. The liquefied tubercle serves as an excellent growth medium for the mycobacteria. The large numbers of extracellular bacilli stimulate delayed-type hypersensitivity, which secondarily causes local damage. The tubercle eventually erodes through the bronchial wall and drains its contents, forming a cavity. The liquified caseous material, teeming with mycobacteria, enters other parts of the lung and the outside environment. The spilling of this liquified material within the lung may produce a caseous bronchopneumonia. 34 The cavity formed at the site of the initial focus remains a significant lesion. Cavities provide optimal conditions for mycobacterial growth. The oxygen tension is increased, and the host s defenses are ineffective at interrupting multiplication of the mycobacteria within a cavity. 34 CLINICAL FEATURES The initial infection with MTB most often is asymptomatic in otherwise healthy persons. Mild fever and malaise may develop in association with the immune response at 4 to 6 weeks, but generally the primary infection is clinically insignificant. 36 Conversion to a positive PPD skin test result may be the only means of diagnosing the infection. Clinically active TB develops in 8 to 10% of otherwise healthy PPD converters who do not take prophylactic agents 3 to 5% in the first 2 years (acute primary TB) and another 5% during the remainder of life (reactivation TB). 19 By contrast, in persons also infected with HIV, progression to acute primary TB occurs at a rate of 37% within 6 months and then to active TB at a rate of 7 to 10% per year. 19 Reactivation of dormant foci is responsible for the major clinical manifestations of TB. 36 Exogenous reinfection of patients with well-documented previous TB infection causes clinical disease indistinguishable from reactivation TB. 37 Because it may be incorrect to label all late-onset cases as reactivation disease, postprimary TB is the preferred term. Postprimary TB is active or chronic disease in a patient previously infected. In the United States and other developed countries, reactivation is thought to be the primary mechanism of postprimary TB. Exogenous reinfection has played a role in circumstances in which contagion levels are high, as in outbreaks of TB, in developing countries, or in immunocompromised hosts Chapter 133 / Tuberculosis

4 1796 Patient s History History of Present Illness Clinically significant pulmonary TB often is indolent, and signs and symptoms are absent or minimal until the disease advances. The patient also may experience a systemic reaction to the infection. The systemic reaction, thought to be mediated by cytokines, especially tumor necrosis factor α, causes the constitutional symptoms of anorexia, weight loss, fatigue, irritability, malaise, weakness, headache, chills, and, most commonly, fever. 36,40 The fever usually develops in the afternoon; defervescence occurs during sleep, leading to the classic night sweats of TB. 36 Cough is the most common symptom of pulmonary TB. Initially it may be nonproductive, but as caseation necrosis and liquifaction develop, mucopurulent and nonspecific sputum typically is produced. 25,36,40 Hemoptysis, caused by caseous sloughing or endobronchial erosion, usually is minor but often indicates extensive lung involvement. 25 Many asymptomatic patients present for medical attention because they are alarmed by the hemoptysis. Patients also may complain of pleuritic chest pain, which is caused by parenchymal inflammation adjacent to the pleural surface. Dyspnea with chest pain may indicate a spontaneous pneumothorax. 41 Shortness of breath from parenchymal lung involvement is unusual, however, and if present indicates extensive parenchymal disease or tracheobronchial obstruction. 36 Table shows the frequency of symptoms found in one study of patients with culture-proven pulmonary TB. 42 The clinical manifestation of TB in patients presenting to the emergency department (ED) may be especially confusing. In one study, only one third of ED patients with active pulmonary TB had pulmonary chief complaints, only 64% ever reported a cough, and only 8% had hemoptysis. 43 Any vague systemic disorder or fever of unknown etiology may represent TB. 19 Atypical presentations are particularly common in infants, the elderly, and immunocompromised persons. In infants and young children, the development of large hilar lymph nodes is common; such nodes may compress a bronchus, leading to atelectasis and possibly obstructive pneumonia; the child may have a brassy cough. A node also PART III Medicine and Surgery / Section Twelve Infectious Diseases Table SYMPTOM/SIGN Frequency of Symptoms and Signs in Pulmonary Tuberculosis NUMBER AFFECTED NUMBER EVALUATED PERCENTAGE AFFECTED Cough Weight loss Fatigue Tactile fever Night sweats Chills Anorexia Chest pain Dyspnea Hemoptysis No respiratory symptoms None of above symptoms From Barnes PF, et al: Chest roentgenogram in pulmonary tuberculosis: New data on an old test. Chest 94:316, may erode through the bronchial wall, causing symptomatic endobronchial disease and allowing endobronchial spread of tuberculous pneumonia to other areas of the lungs. 25 By contrast, fewer elderly persons present with respiratory symptoms. The diagnosis may be masked by coexistent disease and nonspecific presenting symptoms. 44 Pulmonary TB should be considered in elderly patients with chronic cough and failure to thrive. 16 Clinical manifestations of TB in patients co-infected with HIV are even more subtle and nonspecific, especially because these patients are vulnerable to opportunistic infections and neoplasms that can cause the same constitutional symptoms as in TB. A synergy between the two infections (MTB and HIV) leads to a greatly increased viral load. 20 Active TB with HIV co-infection has been associated with an increased risk for opportunistic infections and death. 21 Patients with advanced HIV infection also commonly have extrapulmonary involvement (seen in 30%), as well as combined pulmonary and extrapulmonary TB (in 32%). 40 Risk Factors All patients in the ED who have been coughing should be screened for the presence of TB risk factors 45 (Box 133-1). Risks for acquiring TB may also be stratified by age. Because infants and toddlers have poorly developed cell-mediated immunity, they have a much higher incidence of TB than adults. Children 5 to 10 years of age are relatively resistant to TB. Infants and toddlers commonly have extrapulmonary disease and acute lower and midlung bronchopneumonia that rarely progresses to cavitary disease. Young adults show the adult pattern of apical pulmonary disease, including cavity formation, suggesting reactivation. Because of decreased immunocompetence, elderly persons typically have disease manifestations similar to those in young children. 25 Patients with a history of PPD conversion should be asked about the presence of medical conditions associated with increased risk for the development of active postprimary disease through reactivation 45 (Box 133-2). Patients with a history of active TB should be asked about all antituberculosis medications previously or currently being taken and about compliance. Failure to improve after 2 months on an appropriate regimen may signal nonadherence to therapy or the presence of a resistant strain. 46 BOX Population Groups with Increased Risk for Tuberculosis Close contacts of known case Persons with HIV infection Foreign-born from Asia, Africa, Latin America Medically underserved, low-income populations Elderly persons Residents of long-term care facilities (e.g., nursing homes, correctional facilities) Injection drug users Groups identified locally (e.g., homeless, migrant farmworkers) Persons who have occupational exposure HIV, human immunodeficiency virus. From CDC: TB Care Guide: Highlights from Core Curriculum on Tuberculosis. Atlanta, U.S. Department of Health and Human Services, 1994.

5 1797 BOX Physical Findings Examination of the chest is unlikely to establish the extent of disease. Over areas of infiltration, rales may be heard when the patient breathes in after a short cough (post-tussive rales), and bronchial breath sounds may be present over areas of lung consolidation. Distant, hollow breath sounds that can be heard over cavities are called amphoric breath sounds. 25 One ED study reported abnormal physical examination findings in 80% of patients with active pulmonary TB. 43 Erythema nodosum or phlyctenular keratoconjunctivitis (severe unilateral inflammation of an eye) may appear with the onset of tuberculin hypersensitivity. These self-limited, allergic manifestations are not common in the United States. 25 The patient s overall appearance and state of health may be the most useful indicators in evaluating for the potential presence of TB. General signs include pallor secondary to anemia, fever, and cachexia with weight loss. Complications Pneumothorax Spontaneous pneumothorax is not common (affecting less than 5% of patients with severe cavitary disease) but may occur when a tuberculous cavity ruptures and creates a bronchopleural fistula or when a bleb ruptures into the pleural space 47 (Fig ). Delayed tube thoracostomy and suction result in progressive infection and fibrosis of the pleura that leads to air trapping within affected lung. Empyema Risk Factors for Development of Active Tuberculosis in Previously Infected Persons HIV infection Recent tuberculosis infection (within past 2 years) Chest radiographic findings suggestive of previous untreated tuberculosis Injection drug use Diabetes mellitus Silicosis Prolonged corticosteroid therapy Immunosuppressive therapy Head or neck cancer Hematologic and reticuloendothelial diseases End-stage renal disease Intestinal bypass or gastrectomy Chronic malabsorption syndromes Low body weight (10% or more below the ideal) HIV, human immunodeficiency virus. Modified from CDC: TB Care Guide: Highlights from Core Curriculum on Tuberculosis. Atlanta, U.S. Department of Health and Human Services, An empyema may develop in patients with TB characterized by extensive, progressive parenchymal disease and cavitation. Although rare (with a frequency of 1 to 4%), empyema is more common late in the course of the disease in debilitated patients. Rupture of a cavity into the pleural space usually is catastrophic and often is associated with bronchopleural fistula formation. An untreated empyema can result in spontaneous pleurocutaneous fistula formation, presence of a chest wall mass on the radiograph, or rib and vertebra destruction. 47 Figure Chest radiograph demonstrating cavitary tuberculosis with left-sided pneumothorax. The underlying cause of the pneumothorax was later determined to be a bronchopleural fistula. (Courtesy of John Pearce, MD.) Endobronchial Spread Endobronchial spread is the most common complication of cavitary disease. It is manifested radiographically as 5- to 10- mm, poorly defined nodules clustered in dependent portions of the lungs. These nodules may rapidly coalesce into parenchymal consolidation so-called galloping consumption. 47 Airway Tuberculosis When a cavity drains its highly infectious material into the bronchial tree, the airways not only spread the infection but also develop endobronchial TB. Bronchiectasis commonly complicates endobronchial TB. Bronchial stenosis may result from extensive damage caused by endobronchial TB or from direct extension of infection from tuberculous adenitis or from lymphatic dissemination to the airway. 25,47 Tuberculous bronchostenosis may appear radiographically as persistent segmental or lobar collapse, lobar hyperinflation, and obstructive pneumonia. 47 Tracheal TB and laryngeal TB are less common than endobronchial TB. Laryngeal disease is the most infectious form of TB; it results from the proximal extension of lower airway disease, pooling of infected secretions in the posterior larynx, or hematogenous dissemination to the anterior larynx. Patients with laryngeal TB also usually have active pulmonary disease. 47 Superinfection Extensive TB infection often heals with open cavities and areas of bronchiectasis. 36 Superinfection may occur with a wide variety of organisms, including Aspergillus fumigatus. 48 The characteristic finding on chest radiographs is the aspergilloma or fungus ball (Fig ). Aspergillomas are of particular clinical significance because they may cause massive and fatal hemoptysis. 36 Hemoptysis Mild hemoptysis is a common complication of acute infection. TB also causes massive hemoptysis. The destruction of lung parenchyma leads to rupture of blood vessels. A tuberculous lesion or cavity may erode into a pulmonary artery, leading to Chapter 133 / Tuberculosis

6 1798 PART III Medicine and Surgery / Section Twelve Infectious Diseases Figure Chest radiograph showing superinfection of healed tuberculous cavity. An aspergilloma can be seen in the right upper lung. (Courtesy of John Pearce, MD.) pseudoaneurysm formation (Rasmussen s aneurysm) with potentially fatal hemoptysis. 47 This complication has become uncommon since the development of antituberculosis medications. 25 Alternatively, superinfection of cavities by invasive organisms or tumor development in scarred lung may cause erosion of bronchial or pulmonary vessels, with resultant major hemorrhage. Affected patients often require emergency surgical resection or selective embolization. 49 Primary Tuberculous Pericarditis Primary tuberculous pericarditis usually results from direct extension of infection from the tracheobronchial tree, mediastinal or hilar lymph nodes, sternum, or spine. Pericardial involvement also may result from hematogenous spread secondary to acute miliary TB or from another focus elsewhere in the body. 25,50 In the United States, TB is the leading cause of pericarditis among HIV-infected patients, with a prevalence of up to 15%. 51 The predominant symptoms are cough, chest pain, and dyspnea, and the most common signs are cardiomegaly, an audible rub, fever, and tachycardia. 52 Complications of pericardial TB include pericardial effusion, constrictive pericarditis, myocarditis, and cardiac tamponade. 50 Cardiac tamponade may result from accumulation of pericardial fluid but also may occur if enlarging lymph nodes rupture into the pericardium. Emergency echocardiography reliably confirms the presence of pericardial fluid. 53 DIAGNOSTIC STRATEGIES Laboratory Tests Figure Chest radiographic findings in a child with primary tuberculosis. Note the active Ghon focus with associated hilar adenopathy and presence of bilateral infiltrates. (Courtesy of John Pearce, MD.) Routine laboratory studies generally are not useful in suggesting or establishing the diagnosis. 36 Normochromic normocytic anemia, elevated erythrocyte sedimentation rate and serum globulin level, hyponatremia, and hypercalcemia all can occur in active pulmonary TB, but these findings are nonspecific. 36,48,54 Tuberculin skin testing is important epidemiologically as a modality for diagnosing MTB infection but is of limited value for detecting active clinical disease. At least 20% of patients with active TB have false-negative results on tuberculin skin testing. 25 Diagnostic Imaging Plain radiography of the chest is the most useful study for making a presumptive diagnosis of pulmonary TB. Chest radiographic abnormalities are not limited to the classic upper lobe cavitary infiltrates. Primary TB infection and postprimary disease each have distinctive radiographic features. A normal appearance on the chest radiograph has a high negative predictive value and is therefore useful in screening ED patients for active pulmonary TB. However, the false-negative rate is approximately 1% among immunocompetent adults and increases to 7 to 15% among HIV-positive patients. 24 Therefore, depending on the clinical circumstances, absence of specific abnormalities on the chest radiograph does not always exclude active TB, especially in patients with concomitant endobronchial disease and HIV infection. Primary Tuberculosis Chest radiographic manifestations of primary disease in adults often are not recognized as TB. 55,56 Primary tuberculous infiltrates can occur in any lobe. 47,57,58 With any age group, a pneumonic infiltrate with enlarged hilar or mediastinal nodes should strongly suggest the diagnosis. 57 The infiltrate usually is homogeneous and most commonly involves a single lobe. Thus, primary TB may appear radiographically identical to a bacterial pneumonia, with associated lymphadenopathy, if present, being the only distinguishing feature. Lymphadenopathy is considered the radiologic hallmark of primary TB in children but is seen less commonly in adults. 24,58 When present, adenopathy usually is unilateral and associated with parenchymal infiltrate (Fig ). It may occur bilaterally or, more rarely, may be an isolated finding on chest radiography. 36 Massive hilar adenopathy is more common in young children. As a result, atelectasis, resulting from airway compression by adjacent enlarged nodes, is a likely finding in children younger than 2 years but is less common among older children and adults. 47

7 Other primary TB chest radiographic findings include a moderate to large pleural effusion, which often is an isolated finding whose prevalence increases with age; miliary TB (characterized by the presence of innumerable, 1- to 3-mm noncalcified nodules dispersed throughout both lungs with mild basilar predominance), which is mainly a threat to children younger than 2 years, immunocompromised patients, and the elderly; and tuberculomas, well-circumscribed nodular lesions of the parenchyma thought to be a result of healed primary TB. 24,47 When the healed primary focus is visible on the chest radiograph as a calcified scar, it is known as the Ghon focus. Calcified secondary foci of infection are known as Simon s foci. A Ghon focus associated with calcified hilar nodes is called a Ranke complex. 25,47 A right-sided predominance in the distribution of Ghon s foci and Ranke s complexes is well recognized and probably reflects the higher statistical probability that an air-borne infection will affect the right lung. 24 Calcification seen on the chest radiograph indicates healing, but viable bacilli may still exist in a partially calcified lesion. 57 When resolution does not occur, the result is progressive primary TB, which appears radiographically as progressive parenchymal consolidation often including secondary foci in the upper lobes. 47 In some patients, the primary tuberculous pneumonia breaks down into multiple cavitary lesions or a single large abscess. 57 These chest radiographic findings may easily be confused with the findings in postprimary TB. Postprimary Tuberculosis Postprimary TB typically appears as an upper lung infiltrate or consolidation, with or without cavitation. The lesion may be small or extensive and usually is located in the apical or posterior segment of the upper lobe but may appear in the superior segment of the lower lobe. 59 Postprimary disease also occurs in the lower lung. In addition, bronchogenic spread can occur, leading to involvement of multiple lobes 59 (Fig ). The patient with bilateral upper lobe disease is extremely likely to have TB. 57 The other important, recognizable characteristics of postprimary disease are fibrosis and cavitation The initial lesion of postprimary TB is a poorly defined, heterogeneous alveolar opacity called an exudative lesion. 47 These lesions are not purely exudative in that they are associated with a fibrotic pattern of nodules and a few fine, linear densities. Unchecked, the infection may rapidly progress to lobar or complete lung opacification and destruction. 47 Postprimary TB, however, usually runs a chronic course characterized by reactive fibrosis, and in most cases the initial exudative lesions gradually are replaced by more well-defined reticular and nodular opacities or fibroproductive lesions. 47,57 Fibroproductive lesions often are irregular and angular in contour, have strands extending toward the hilum, and demonstrate calcification of one or more nodules. This pattern is characteristic of granulomatous disease and rarely is found in other bacterial infections. 31 As fibrosis continues, distortion of normal vascular and mediastinal structures secondary to contraction and shrinkage of the scar may be apparent. Severe fibrosis with upper lobe volume loss may eventually lead to retraction of the interlobar fissure and upward displacement of the hilum. 57 The chest radiographic appearance at this stage has been variably referred to as old scarring, no active disease, or fibrotic, apparently well-healed TB. Many of the patients have positive sputum culture results, and infectivity cannot be accurately assessed by chest radiography. 47,57 Only serial radiographs can reliably differentiate active from inactive disease. Lack of radiographic changes over a 4- to 6- month interval generally indicates inactive or, more precisely, radiographically stable disease. 24 Cavitation should alert ED personnel to the high infectivity of the patient and the potential for associated complications such as bronchogenic spread of TB when an area of caseous necrosis liquefies, with consequent communication with the bronchial tree (see Fig ). Cavities usually are multiple and range in diameter from a few millimeters to several centimeters. 47 The walls of the cavities initially are thick and rough and become thinner and smoother with healing (Fig ). A hazy, parenchymal reaction around a cavity with an illdefined wall strongly suggests an active lesion. Most cavities heal by obliteration, often leaving a small linear or stellate scar; others remain patent and become thin-walled bullae. 57 Chapter 133 / Tuberculosis Figure Chest radiograph showing evidence of right upper lobe cavitary disease. Also note the left-sided infiltrate, secondary to endobronchial spread. Figure A healed, thin-walled cavity can be seen in the left upper lobe on this chest film. (Courtesy of John Pearce, MD.)

8 PART III Medicine and Surgery / Section Twelve Infectious Diseases 1800 Although pulmonary TB usually induces chest radiographic changes, patients with sputum cultures positive for MTB may nevertheless demonstrate normal radiographic findings. In a series of 103 patients, 10 people (9.7%) with confirmed pulmonary TB had normal findings on their chest radiographs. 56 Chest radiographs also may be normal in appearance in patients with endobronchial TB. 41,60 Chest radiographs of patients with pulmonary TB and HIV infection may be atypical in approximately one third of cases. 61 However, the radiographic appearance of disease is heavily influenced by the degree of immunocompromise. Patients with late HIV infection more often demonstrate mediastinal adenopathy or atypical infiltrates and less often have cavitation. 62,63 Severe immunosuppression has been reported to be associated with a miliary pattern of disease on chest radiographs. 24 Conversely, chest radiographs of patients with early HIV infection are more similar to those of patients without HIV infection, with upper lobe infiltrates, more cavitation, and less adenopathy. 64 A normal chest radiographic appearance also is common in patients with HIV infection. In one study, chest radiographic findings were normal in 14% of HIV-infected patients, including 21% of those with CD4 + counts below 200/µL and 5% of those with CD4 + counts greater than 200/µL. 61 Microbiology Sputum Studies If the clinical or chest radiographic findings suggest the diagnosis of pulmonary TB, mycobacteriologic studies of the patient s sputum should be ordered. Spontaneously produced sputum collected under direct supervision is preferred, and early-morning samples are the best diagnostic specimens. 25 Classically, three initial sputum specimens should be obtained on different days. A positive smear s a presumptive diagnosis, and the number of bacilli seen correlates with infectivity. For patients who are not producing sputum, nebulized induction of sputum and gastric aspiration of swallowed respiratory secretions are the methods of choice for collecting samples. 65 The diagnostic yield is higher for nebulizer-induced sputum samples than for gastric aspirates in adult patients with TB, but in some patients, especially children, gastric aspirates may be the only obtainable specimens. Induction of sputum with nebulization may increase the risk of TB transmission to health care workers and should be performed only in specially ventilated rooms, preferably not in the ED. When sputum is not diagnostic in adults, fiberoptic bronchoscopy with bronchial washings, brushings, and bronchoalveolar lavage or transbronchial biopsy may be necessary for laboratory diagnosis of TB. 65 In children, sputum obtained by bronchoscopy has a lower culture yield, so this technique is used less often to obtain sputum from pediatric patients. 66 Direct Microscopy Direct microscopic examination of a stained sputum specimen for AFB (i.e., an AFB smear) is the most rapid laboratory test widely available to a presumptive diagnosis of TB (Fig ), and results usually are available within 24 hours. 67 Although nontuberculous mycobacteria can cause pulmonary disease, they are less common than MTB and vary by geographic location and population of patients. Fluorochrome stains are more sensitive than the traditional Ziehl-Neelsen or Kinyoun methods for the detection of AFB from clinical specimens. 66,67 Negative findings on an AFB smear, however, do not rule out active pulmonary TB, because microscopy is relatively Figure Photomicrograph of an acid-fast bacillus smear of Mycobacterium tuberculosis. (Courtesy of Alfredo Ponce de Leon, MD.) insensitive when performed on samples with small numbers of bacilli. At least 5000 bacilli/ml of sputum must be present for a positive result by microscopy. 67 Because cavitary disease is associated with great numbers of bacilli, the diagnostic yield of microscopy increases with cavitation. Concentrated smears are prepared by decontamination, liquefaction, and centrifugation of sputum, and such smears may be more sensitive than unconcentrated samples. 14 Overall, AFB smears have a sensitivity of 20 to 80% and a specificity of 90 to 100%. 67 Despite its limitations, microscopy remains an essential diagnostic test because of its ease of performance, low cost, rapid turnaround time, and reasonable diagnostic yield. Culture A presumptive diagnosis of TB based on a positive sputum smear usually is confirmed by isolating MTB by culture. Traditional culture methods using solid media require 3 to 8 weeks for colony formation. The development of liquid culture systems has shortened the detection time to 7 to 14 days. A number of liquid culture systems are available for detection of MTB. For example, the BACTEC (Becton Dickinson, Franklin Lakes, NJ) method measures 14 CO 2 produced by growing mycobacteria when they metabolize the 14 C-labeled palmitic acid contained in the system, and the mycobacteria growth indicator tube (MGIT) method measures mycobacterial oxygen consumption with a fluorescence assay. 67 Sputum culture is more sensitive than microscopy for detecting MTB and is still considered the gold standard diagnostic modality. Liquid culture can detect 10 to 100 bacilli/ml, compared with 5000 to 10,000 bacilli/ml for AFB smear. When the presence of mycobacteria is established, the specific identification of MTB may be accomplished by subjecting the initial mycobacteria to various isolation techniques. These include the detection of pigmentation on solid culture media, various biochemical tests, high-performance liquid chromatography, and nucleic acid probes. 67 Drug Susceptibility Testing Because of the emergence of multidrug-resistant MTB, all initial isolates of MTB should be tested for susceptibility to isoniazid (INH), rifampin (RIF), and ethambutol (ETH). 68 Further susceptibility testing should be performed when resistance to one of the three agents is detected or if the patient has had previous TB treatment, has been exposed to a drug-

9 resistant contact or source, or has demonstrated a positive result on sputum cultures beyond 3 months of therapy. 68 Conventional susceptibility testing detects selective growth of drug-resistant TB on media containing antituberculosis drugs. For first-line agents, this requires waiting until 4 to 7 days after a positive culture result is obtained; testing for susceptibility to other drugs may require 2 to 3 months. The BACTEC and MGIT systems also can be used for rapid drug susceptibility testing, with resluts obtained in fewer than 12 days. 67 Other new approaches to susceptibility testing include flow cytometry, genotypic sequence based methods, and bacteriophage viability testing. 67,69 Nucleic Acid Amplification Tests A number of nucleic acid amplification assays are available to assist in the rapid diagnosis of MTB infection, including polymerase chain reaction (PCR) tests, the Mycobacterium tuberculosis direct test (MTDT), and the ligase chain reaction. 67 These tests can be used directly on clinical specimens but at present are of limited utility in the diagnosis of MTB. They are undergoing refinement, however, and may become valuable tools in the future. Problems include high cost and potential for suboptimal performance in clinical settings because of factors such as variability in laboratory methodology, potential for specimen contamination, and lower-than-expected sensitivity. 14,66 Sputum smears are still needed to evaluate for infectiousness, because these tests are unable to differentiate active from treated infection. Sputum cultures also are still needed, because these tests do not assess drug susceptibility. 14 Nucleic acid amplification tests may be useful, however, when findings on standard clinical and microbiologic tests are negative or inconclusive. The PCR assay may provide a method for confirming the diagnosis of TB within a few hours. PCR testing is based on a DNA amplification technique that bypasses the delays inherent with mycobacterial cultures. It allows the in vitro synthesis of millions of copies of a specific MTB DNA segment. 70 Diagnostic techniques based on PCR allow direct testing of routine clinical specimens to confirm the diagnosis of TB in hours. Test performance varies greatly, depending on whether the sputum sample is AFB smear positive or negative. For example, for AFB smear positive specimens, the Roche (Roche, Nutley, NJ) Amplicor system has a sensitivity of 95 to 96% and specificity of 100%. When it is applied to AFB smear negative specimens, the sensitivity drops to 48 to 53%, with a specificity of 96 to 99%. 67,71 The MTDT enzymatically amplifies a 16S ribosomal RNA (rrna) segment that is specific for MTB complex species. Preliminary studies suggest that the MTDT has excellent sensitivity (86 to 98%) and specificity (97 to 100%) for the rapid identification of MTB and can be performed in approximately 5 hours. As with PCR assays, specimen quality and the degree of AFB smear positivity affect test performance. 67,72 The Ligase Chain Reaction The ligase chain reaction amplification assay involves repetitive cycles of high-temperature DNA denaturation, oligonucleotide annealing, and ligation. The Abbott Laboratories (Abbott Park, IL) LCx assay has a sensitivity of 98% for AFB smear positive specimens and 27% for AFB smear negative specimens and a specificity of 100% (equal to that of culture). 67 When LCx was compared with PCR assay and MTDT in a clinical trial, no significant difference in sensitivity or specificity was found among these three tests. 73 Tuberculostearic acid (TSA) is a fatty acid found only in mycobacteria. It can be detected with gas chromatography mass spectrometry in clini cal specimens containing small numbers of bacilli. TSA testing is not frequently used, because the equipment and expertise needed to run this test are not widely available outside specialized research laboratories. 74 Interferon-γ Levels IFN-γ is a cytokine associated with cell-mediated immunity. Determination of IFN-γ levels also can be used as a diagnostic test for tuberculous pleural effusions, ascites, and pericardial effusions. Clinical studies have reported sensitivity and specificity of 100% and 100%, respectively, for assay of IFN-γ in pericardial fluid and 78% and 97% in pleural fluid. 75,76 IFN-γ assay can be used independently, as a confirmatory test, or in combination with other tests, such as PCR assay. 76 Serology Serodiagnosis of TB, if such testing were readily available, would be a minimally invasive approach to rapid diagnosis. Using an enzyme-linked immunosorbent assay (ELISA) to diagnose TB from serum would be especially useful in patients who cannot produce sputum. Although ELISAs have been developed for several MTB antigens, in practice, no serodiagnostic approach to the diagnosis of TB currently is in widespread clinical use in the United States. Limitations of the ELISA include inadequate accuracy and reproducibility, inability to distinguish active from latent infection, poor discrimination between MTB and other mycobacteria, and relative cost. 66,67 Tuberculin Skin Test While newer diagnostic tests undergo development, the tuberculin skin test remains the best tool available for detecting latent MTB infection. The tuberculin test is based on the principle that MTB infection induces sensitivity to certain antigens of the bacillus. These antigens are contained in the tuberculin preparation called PPD. In a person infected with TB, the PPD test result usually turns positive 3 to 8 weeks after the infection, when the immune response is developed. 25 The standard 0.1-mL dose used in skin testing contains 5 tuberculin units (TU). This dose is administered intradermally with the needle bevel up, using the Mantoux technique. A properly placed needle should leave a blanched, distinct wheal 6 to 10 mm in diameter. 45 If the tuberculin dose is incorrectly administered, the test may be repeated immediately at a site several centimeters away. Various types of test kits and applicators are available (Heaf and tine tests), but for diagnostic purposes the Mantoux test with PPD (5 TU) is preferred. 29,66,77 Tests are read 48 to 72 hours after of PPD. The largest diameter of palpable induration is measured and recorded in millimeters; erythema by itself is not measured. The precise measurement that denotes a positive test result depends on the patient s other clinical factors. The current CDC guidelines use 15 mm of induration as a positive test for people without TB risk factors 78 (Table 133-2). Some persons with previous TB infection gradually lose their hypersensitivity reaction to PPD and may react weakly or not at all. The PPD test, however, can restimulate or enhance their hypersensitivity, so that a subsequent test does elicit a positive reaction. This phenomenon is called the booster effect. This boosted reaction may be mistaken for a new infection. To eliminate the booster effect as a confounding factor, a two-step testing method is recommended for Chapter 133 / Tuberculosis

10 1802 PART III Medicine and Surgery / Section Twelve Infectious Diseases Table SIZE OF REACTION Criteria for a Positive Tuberculin Skin Test Result PERSONS IN WHOM REACTION IS CONSIDERED POSITIVE 5 mm HIV-infected persons Close contacts of persons with infectious tuberculosis Persons with abnormalities on chest radiograph consistent with previous tuberculosis* Immunosuppressed patients receiving the equivalent of 15 mg of prednisone per day for 1 month 10 mm Foreign-born persons recently arrived ( 5 years earlier) from a country with a high prevalence of tuberculosis Persons with a medical condition that increases the risk of tuberculosis Injection drug users Members of medically underserved, lowincome populations (e.g., homeless persons) Residents and staff members of long-term care facilities (e.g., nursing homes, correctional institutions, homeless shelters) Health care workers Children <4 years of age Persons with conversion on a tuberculin skin test (increase in induration of 10 mm within a 2-year period) 15 mm All others *Chest radiographic abnormalities consistent with previous tuberculosis consist of fibrotic opacities occupying more than 2 cm 2 of the upper lobe; presence of pleural thickening or isolated calcified granulomas is not considered to be suggestive of previous tuberculosis. Medical conditions that increase the risk of development of tuberculosis in the presence of latent tuberculosis infection include silicosis, end-stage renal disease, malnutrition, diabetes mellitus, carcinoma of the head and neck or lung, immunosuppressive therapy, lymphoma, leukemia, loss of more than 10% of ideal body weight, gastrectomy, and jejunoileal bypass. These persons should not be screened in the absence of an indication. HIV, human immunodeficiency virus. From Jasmer RM, Nahid P, Hopewell PC: Latent tuberculosis infection. N Engl J Med 347:1860, BOX Factors Causing Decreased Ability to Respond to Tuberculin Factors Related to Person Being Tested Infections Viral (e.g., measles, mumps, chickenpox) Bacterial (e.g., typhoid fever, brucellosis, typhus, leprosy, pertussis, overwhelming tuberculosis, tuberculosis pleurisy) Fungal (e.g., South American blastomycosis) Live virus vaccinations (e.g., measles, mumps, polio) Metabolic derangements (e.g., chronic renal failure) Nutritional factors (e.g., severe protein depletion) Diseases affecting lymphoid organs (e.g., Hodgkin s disease, lymphoma, chronic lymphocytic leukemia, sarcoidosis) Drugs (corticosteroids and many other immunosuppressive agents) Extremes of age (newborns, elderly with waning sensitivity) Recent or overwhelming infection with Mycobacterium tuberculosis Systemic stress (surgery, burn injury, mental illness, graft-versus-host reactions) Factors Related to Tuberculin Used Improper storage (exposure to light and heat) Improper dilutions Chemical denaturation Contamination Adsorption (partially controlled by addition of Tween 80) Factors Related to Method of Administration Injection of too little antigen Delayed after antigen has been drawn into syringe Injection site too close to control Factors Related to Reading and Interpreting Test Results Inexperience of reader Conscious or unconscious bias Error in recording persons who undergo serial PPD screening (health care workers). If the result of the first test is negative and the person does not have a documented negative PPD test result during the previous 12 months, a second test is done 1 week later using the same dose. If the second test is positive, it is most likely to represent a boosted reaction and the person should be considered previously infected. If the second test result remains negative, the person is considered uninfected and a positive reaction to a subsequent test indicates new infection. 29 Infection with nontuberculous mycobacteria may cause a false-positive PPD result. These reactions tend to be smaller than the true-positive reaction to MTB infection. Similarly, bacille Calmette-Guérin (BCG) vaccination may produce a PPD reaction that generally is mild and deteriorates with time. A large reaction to PPD and a long time interval between BCG vaccination and the current skin test make it more likely that the reaction is due to MTB infection. 29 Because the BCG vaccine is imperfect in protecting against MTB infection and because most vaccinated persons come from areas of high TB prevalence, the CDC recommends that tuberculin skin test results be interpreted without regard to BCG vaccination status. 79 Many conditions can lead to false-negative reactions to PPD testing (Box 133-3). The incidence of false-negative results in one study was 25% among the 200 patients with active TB. 25 Therefore, the clinical significance of a negative PPD result is best determined by considering other clinical factors. Despite some limitations, PPD skin testing remains useful to diagnose individual patients, to screen populations, and to evaluate infected persons for prophylactic treatment 78 (Table 133-3). DIFFERENTIAL CONSIDERATIONS Pulmonary Tuberculosis Bacterial Pneumonia Segmental or lobar infiltrates on chest radiographs in bacterial pneumonia may easily be confused with those seen in TB, especially primary disease. Compared with TB, however, bacterial pneumonias usually arise with more profound symptoms of systemic toxicity, a more acute onset, and an elevated white blood cell count. 48 In pulmonary TB, there is no prompt response to antibiotics, as seen in bacterial pneumonia. 25

11 Table RISK COMPONENT Increased risk of exposure to infectious cases Increased risk of tuberculosis infection Increased risk of active tuberculosis once infection has occurred Persons at Increased Risk Who Should Be Tested for Latent Tuberculosis Infection EXAMPLES OF PERSONS WITH RISK Persons with recent close contact with persons known to have active tuberculosis* Health care workers who work at facilities where patients with tuberculosis are treated Foreign-born persons from countries with a high prevalence of tuberculosis Homeless persons Persons living or working in facilities providing long-term care HIV-infected persons Persons with recent tuberculosis infection Injection drug users Patients with end-stage renal disease Patients with silicosis Patients with diabetes mellitus Patients receiving immunosuppressive therapy Patients with hematologic cancers Malnourished persons or those with a recent weight loss of more than 10% of their ideal body weight Persons who have undergone gastrectomy or jejunoileal bypass *We define close contact as at least 12 hours of contact with a person with infectious tuberculosis, but well-established criteria for such contact are lacking. Persons with recent infection include children younger than 4 years and persons found to have tuberculin conversion, defined as an increase in induration of at least 10 mm on a tuberculin skin test within a 2-year period. HIV, human immunodeficiency virus. From Jasmer RM, Nahid, P, Hopewell PC: Latent tuberculosis infection. N Engl J Med 347:1860, Fungal and Nontuberculous Mycobacterial Infections Histoplasmosis, coccidioidomycosis, and blastomycosis, as well as nontuberculous mycobacterial infections (mainly with Mycobacterium avium complex and Mycobacterium kansasii), may be radiologically indistinguishable from TB. 80 The incidence of these infections is influenced by geographic location. 48,81 Nontuberculous mycobacterial infection most commonly involves chronic pulmonary infection in HIV-infected patients. 82 Immunocompetent persons also may become infected with MTB, especially patients with chronic lung disease such as cystic fibrosis. Other important risk factors include work in the mining industry, warm climate, advancing age, and male gender. 83 Pneumonias in Patients with Human Immunodeficiency Virus Bacterial pneumonias including upper lobe Pneumocystis pneumonia (due to Pneumocystis jiroveci) and, rarely, Nocardia and Rhodococcus infections may mimic TB in patients with HIV infection. 54 Cavitary Lesions Lung abscess or cavitating pneumonia caused by Klebsiella pneumoniae, Staphylococcus pyogenes, or aspiration may appear similar to cavitary TB on chest radiographs. 48 In older patients, especially smokers, bronchogenic carcinoma may mimic TB; this is particularly true of squamous cell carcinoma, which 1803 tends to cavitate. 48 Because cancer may cause a focus of TB to spread, the two diseases may be present simultaneously. 36 Other causes of nontuberculous cavitary lesions include M. avium complex infection in HIV-negative patients, pulmonary infarction secondary to pulmonary embolus, Wegener s granulomatosis, and upper lobe bullous disease secondary to emphysema or neurofibromatosis. 48,54,82 Upper Lobe Infiltrate with and without Fibrosis A radiographic pattern characterized by presence of an upper lobe infiltrate with or without fibrosis may be seen with atypical mycobacteria, ankylosing spondylitis, silicosis, collagen vascular diseases, lymphomas, and actinomycosis. 54 Upper zone fibrosis and volume loss can occur in the later stages of extrinsic alveolitis, allergic bronchopulmonary aspergillosis, and sarcoidosis. The presence of calcification suggests TB. 48 Mediastinal Lymphadenopathy The main considerations in the differential diagnosis for adenopathy include lymphoma and sarcoidosis. In sarcoidosis, lymphadenopathy usually is bilateral, symmetrical, and asymptomatic. Lymphadenopathy in TB tends to be unilateral or, if bilateral, is asymmetrical and associated with parenchymal lung disease. Lymphoma tends to involve very bulky mediastinal lymphadenopathy. 48 Extrapulmonary Tuberculosis Tuberculous infection involving multiple sites most commonly is seen in patient populations less capable of containing MTB infection such as infants, the elderly, and immunocompromised persons. 40 Extrapulmonary TB accounted for roughly 15% of newly diagnosed TB cases in the United States before the HIV epidemic. As reported in 2002, approximately 21% of TB patients in the United States had extrapulmonary disease, and another 7.5% had both pulmonary and extrapulmonary infection. 17 In children younger than 4 years, approximately 25% of TB infections are extrapulmonary. 66 Among HIVinfected persons, extrapulmonary TB infection becomes progressively more common as CD4 + counts fall below 350 cells/µl. 63 One study of patients with TB concurrent with advanced HIV infection reported that 38% had only pulmonary disease, 30% had extrapulmonary TB alone, and 32% had both pulmonary and extrapulmonary TB. 40 Extrapulmonary TB may occur in multiple sites, with relative frequencies of 42% for lymphatic, 18% for pleural, 12% for bone or joint, 6% for genitourinary, 6% for meningeal, 5% for peritoneal, and 11% for other sites. 17 The lymph nodes are the most common site of extrapulmonary TB for both otherwise normal and HIV-infected patients. Involvement of the meninges is more common in young children than in other age groups (present in approximately 4% of children with TB), and the incidence of TB in the remainder of the extrapulmonary sites increases with age. 40,66 Less commonly involved locations for extrapulmonary TB include the skin, heart, pericardium, thyroid gland, mastoid cells, sclerae, and adrenal glands. Lymphadenitis Tuberculous lymphadenitis (scrofula) is the most common form of extrapulmonary TB. Scrofula is common in children but most commonly is seen in young adult women, usually of minority races. 25 The patient usually has an enlarging, painless, red, firm mass in the region of one or more lymph nodes, most commonly in the anterior or posterior cervical chain or the supraclavicular fossa. Early on, the nodes are discrete, rubbery masses that are freely mobile, and the overlying skin is normal. Eventually, the nodes may become matted and Chapter 133 / Tuberculosis

12 PART III Medicine and Surgery / Section Twelve Infectious Diseases 1804 harder and the overlying skin inflamed. Fluctuance may be present, as well as an abscess or sinus tract if a node erodes through the skin. 84 Systemic signs and symptoms are uncommon, except in HIV-positive patients, in whom lymphadenitis usually is generalized. 40 Pulmonary infection is present in only 10 to 20% of cases. 84 Considerations in the differential diagnosis include lymphoma, metastatic cancer, fungal disease, catscratch disease, sarcoid, toxoplasmosis, reactive adenitis, and bacterial adenitis. The diagnosis of scrofula usually is made by fine needle aspiration of an affected lymph node. Although AFB smears are positive in only approximately 20% of cases, granulomatous inflammation may be obvious. Overall, fine needle aspiration has a sensitivity of 77% and specificity of 93% for TB infection. First-line treatment of scrofula consists of antituberculosis drugs, but surgical excision may be performed when medical therapy has failed or if the diagnosis is unclear. Incision and drainage should not be done because permanent sinuses and prolonged drainage can result. 84 Pleural Effusion Pleural extrapulmonary TB may occur early after primary infection with MTB and manifest as pleurisy with effusion, or more rarely, it may occur late in postprimary cavitary disease and arise as an empyema. Tuberculous pleural involvement often causes no symptoms and resolves spontaneously; however, in untreated patients, a 65% relapse rate has been reported, with development of active pulmonary or extrapulmonary TB within 5 years. Dyspnea may occur if the effusion is large, but the effusions usually are small and unilateral. Often the presentation is acute, severe, and indistinguishable from that of a bacterial pneumonia. In the elderly, however, the onset may be more insidious and likely to be confused with congestive heart failure, cancer, or a pulmonary embolus. 25 The diagnosis usually is confirmed by microscopic and chemical examination of pleural fluid or pleural biopsy. White blood cell counts usually range from 500 to 2500 cells/ml. The fluid is an exudate with protein usually exceeding 50% of the serum protein, and the glucose may be normal to low. Because there are few bacilli, AFB smears rarely are positive, and cultures grow MTB for only 25 to 30% of patients known to have the disease. Pleural biopsy can confirm the diagnosis in approximately 75% of patients. 25 Bone and Joint Infection Bone and joint TB remains a disease of older children and young adults in developing countries, and it is increasingly a disease of adults in developed countries. 25 Skeletal TB presumably develops from reactivation of dormant tubercles originally seeded during stage 2 of the primary infection or, in the case of spinal TB, from contiguous spread from paravertebral lymph nodes to the vertebrae. Generally, spinal TB (Pott s disease) accounts for 50 to 70% of the reported cases; the hip or knee is involved in 15 to 20% of cases, and the ankle, elbow, wrists, shoulders, and other bones and joints account for 15 to 20% of cases. 40 Approximately 50% of patients have a previous history or concurrent case of pulmonary TB, and the chest radiograph is normal in appearance in up to one half of the cases. Patients with Pott s disease may simply complain of back pain or stiffness. Examination may show fever, point tenderness, and decreased range of motion. If the initial radiograph is normal in appearance, the diagnosis may be delayed, allowing the disease to progress. The initial lesion usually spreads to the intervertebral disk and then to the adjacent vertebrae, producing the classic radiographic appearance of anterior wedging of two involved vertebral bodies with destruction of the disk. Early changes of spinal TB can be difficult to detect on plain radiographs and include loss of the white stripe of the vertebral end plate subsequent to destruction of subchondral bone. Unfortunately, plain films usually are unable to reveal TB infection until roughly 50% of the vertebra has been destroyed. 85 Thus, computed tomography (CT) and magnetic resonance imaging (MRI) scanning should be used when the disease is suspected. 25,40 Paraspinal cold abscesses develop in 50% or more of cases, with occasional formation of sinus tracts. The abscess can spread the infection up and down the spine, sometimes sparing vertebral bodies along its course, forming the so-called skip lesions. 25,85 These skip lesions can easily be missed in imaging the spine for Pott s disease. The main complication of Pott s disease is spinal cord compression. 40 Medical management includes chemotherapy, modified bedrest, and early ambulation and results in improvement in approximately 90% of patients without neurologic involvement. 25 Surgical treatment usually is reserved for patients with neurologic complications. Renal Disease The kidney is well vascularized, and hematogenous dissemination to that organ is fairly common. After the typical tuberculous lesions develop within the parenchyma, infection can spread into the calyces, renal pelvis, ureters, and bladder. As a result, tuberculous granulomas, scarring, and obstruction can occur anywhere along the urinary tract. 86 The initial presenting signs and symptoms of urinary involvement are nonspecific. Advanced renal disease and destruction may occur before the diagnosis is made. The urinalysis often reveals pyuria, hematuria, and albuminuria. Sterile pyuria is a classic finding in renal TB, but in many cases with this finding, cultures will be positive for other urinary pathogens. The finding of pyuria in an acid urine with no organisms isolated should increase clinical suspicion for TB. 40 In one study of the diagnosis of renal TB, AFB stains were found to be 52% sensitive and PCR testing was 96% sensitive. 87 Both tests had excellent specificity (97 to 98%). Mycobacterial cultures should be ordered when genitourinary TB infection is suspected. Complications of renal TB include nephrolithiasis, ureteral obstruction or reflux, recurrent bacterial infections, hypertension, papillary necrosis, renal insufficiency, autonephrectomy, and, rarely, development of transitional cell cancer. 86,87 Male Genital Disease Male genital TB usually is associated with coexistent renal TB. Spread of infection from the kidney may involve the prostate, seminal vesicles, epididymides, and testes. 25 A painless or slightly painful scrotal mass is a typical finding, and the patient may have symptoms of prostatitis, epididymitis, or orchitis. 40 Epididymal or prostatic calcifications may be clues to the diagnosis. TB involvement of the seminal vesicles may lead to infertility. 87 Female Genital Disease In women, the disease usually begins with a hematogenous focus in the fallopian tubes. The infection then spreads to the endometrium (in 50%), ovaries (in 30%), cervix (in 5 to 15%), and vagina (in 1%). 25 Clinical manifestations may include abdominal or pelvic pain, ascites, infertility, menstrual irregularities, and, rarely, vaginal discharge. An ulcerating mass may be present on the cervix. Genital TB may be confused with ovarian or endometrial cancer, Meigs syndrome, vulvar or vaginal ulcer, pelvic abscess, cervicitis, or cervical carcinoma. 88

13 Sexual transmission of TB by persons with active genital TB has been described. 89 Women with genital TB who become pregnant are at increased risk for ectopic pregnancy. 25 Multisystem Disease Acute disseminated TB refers to active hematogenous spread of MTB to several organs in the body. The term miliary tuberculosis was first used to describe the pathologic lesions, which resemble small millet seeds. This term is now used as a clinical term referring to the massive dissemination that leads to generalized systemic illness. Miliary TB occurs when the host is unable to contain either a recently acquired or a dormant TB infection. In the past, miliary TB occurred mainly in young children after primary infection; today, it is more common in the elderly and in persons infected with HIV. 40 In infants and young children, the illness generally is acute and severe. In young adults, the acute illness runs a slower course and usually is less severe. Miliary TB often is a subtle disease associated with alcoholism, cirrhosis, neoplasm, pregnancy, collagen vascular disease, or use of corticosteroids or immunosuppressive medications. 25 The clinical presentations are varied because of the multisystem nature of miliary TB. Systemic symptoms of fever, weight loss, anorexia, and weakness generally are present. 40 The choroidal tubercle (a granuloma in the choroid of the retina) may represent the only physical finding specific for disseminated TB. 40 A presumptive diagnosis can be made rapidly if chest radiographs show a miliary infiltrate (Fig ). Unfortunately, the classic miliary pattern is absent on radiographs in approximately 50% of cases. Routine laboratory tests generally are not helpful. Hyponatremia from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is common and often is associated with meningitis. Panculturing usually has a high yield, and HIV-infected patients may have positive results on blood cultures. Transbronchial biopsy can be performed to obtain tissue rapidly for analysis. Other potential biopsy sites include liver, lymph nodes, and bone marrow. 25 Mortality rates for miliary TB are higher than for the other forms of TB, with one case series reporting a rate of 21%. 90 The high mortality rate often is caused by delay in treatment, which should always be initiated immediately on the basis of clinical suspicion and not delayed until confirmation of the diagnosis. A fulminant form of miliary TB may cause the acute respiratory distress syndrome and disseminated intravascular coagulation. In these cases, the addition of corticosteroids (prednisone, 60 to 80 mg/day) is indicated. 25 Central Nervous System Disease Approximately 6% of all cases of extrapulmonary TB involve the central nervous system (CNS), 17 and CNS involvement remains a grave consequence of tuberculous infection. The 1805 peak incidence of CNS TB is in newborn to 4-year-old children. 40 Tuberculous Meningitis Tuberculous meningitis usually results from the rupture of a subependymal tubercle into the subarachnoid space, rather than from direct hematogenous seeding of the CNS. 25 When it is a complication of miliary TB, meningitis usually develops within several weeks. In children, it is an early postprimary TB event, usually appearing within 6 months. Tuberculous cerebral involvement is most marked at the base of the brain, and vasculitis of local arteries and veins may lead to aneurysm formation, thrombosis, and focal hemorrhagic infarction. The vessels to the basal ganglia most commonly are involved, leading to formation of lacunar infarcts or deficits associated with movement disorders. Involvement of other vessels, such as the middle cerebral artery, may lead to hemiparesis or hemiplegia. 25 Tuberculous meningitis begins with a prodrome of malaise, headache, and low-grade fever. In 2 to 3 weeks, a protracted headache develops. Vomiting, confusion, meningismus and focal neurologic signs, and coma may follow. Nuchal rigidity may be absent. Diplopia resulting from basilar exudate is present in up to 70% of patients. Hyponatremia may be present because SIADH is common. The CSF cell count usually ranges from 0 to 1500 white blood cells per ml, with a predominance of lymphocytes; however, polymorphonuclear cells may predominate early in the course. CSF protein usually is elevated and CSF glucose typically is low. A single lumbar puncture CSF specimen yields a positive AFB culture result in only 37% of cases, but pooled samples from multiple lumbar punctures 4 yield a positive result in 90% of cases. 25 The classic triad of neuroradiologic findings in patients with TB meningitis consists of basal meningeal enhancement, hydrocephalus, and cerebral or brainstem infarction. CT or MRI also may reveal rounded lesions typical of evolving parenchymal tuberculomas. 91 Prognosis is influenced by age, duration of symptoms, and the presence of neurologic deficits. In children, the overall mortality is 13%, and permanent neurologic deficits develop in approximately one half of the survivors. 66 Outcome also is closely linked to the clinical stage at which the disease arises. Complete recovery is the rule in stage 1, wherein the alert patient has no focal neurologic signs and no hydrocephalus. Stage 2 is characterized by confusion and focal neurologic changes, and patients in stage 3 present with stupor or with dense hemiplegia or paraplegia. In contrast with the excellent prognosis for stage 1 disease, approximately one half of patients with stage 3 disease either die or are left with severe neurologic disability. 25 Treatment starts with a four-drug regimen. INH and pyrazinamide (PZA) reach increased concentrations in the CSF in the presence of inflamed meninges. RIF also crosses the Chapter 133 / Tuberculosis Figure Chest radiograph (A) and CT image (B) demonstrate a miliary pattern. (Images reprinted with permission from Extrapulmonary tuberculosis: An overview, November 1, 2005, American Family Physician. Copyright 2005 American Academy of Family Physicians. All rights reserved.) A B

14 PART III Medicine and Surgery / Section Twelve Infectious Diseases 1806 blood-brain barrier. Whereas for most other forms of extrapulmonary TB, 6-month regimens are used, the CDC recommends 9 to 12 months of therapy for TB meningitis. 68 Corticosteroids also are recommended by the CDC. Prednisone, 60 to 80 mg, should be given in a daily dose and tapered over 4 to 6 weeks. 25 Ventricular shunting may be needed if hydrocephalus develops. Spinal Meningitis Tuberculous spinal meningitis is a complication of CNS infection that usually originates through hematogenous dissemination from an outside source, although tuberculous meningitis may extend caudally and involve the spine. Local extension of bone or disk TB also has been described. Presenting symptoms and signs result from nerve root or cord compression and may include pain, sensory changes, paralysis, or weakness of bladder or rectal sphincters. 25 Intracranial Tuberculoma A tuberculoma usually begins in an area of TB cerebritis as a cluster of microgranulomas, which coalesce into a mature noncaseating granuloma. 91 These space-occupying lesions may cause focal or generalized signs or symptoms, such as tonicclonic seizures. Involvement of the CNS parenchyma also may be accompanied by meningitis. Imaging reveals either solitary or multiple tuberculomas (Fig ), usually involving the frontal or parietal lobes. 91 Treatment includes chemotherapy before surgical removal. Corticosteroids may reduce edema and decrease the symptoms. If MTB is discovered at the time of surgery, postoperative chemotherapy may prevent the further spread of the disease. 25 Gastrointestinal Disease Gastrointestinal TB infection usually is secondary to hematogenous or lymphatic spread but also may result from swallowed bronchial secretions or direct spread from local sites, such as lymph nodes or fallopian tubes. 92 TB may occur in any gastrointestinal location from the mouth to the anus, but lesions proximal to the terminal ileum are rare. The ileocecal area is the most common site of involvement, producing signs and symptoms of pain, anorexia, diarrhea, obstruction, hemorrhage, and often a palpable mass. Figure Head computed tomography scan demonstrating tuberculomas in a patient with acquired immunodeficiency syndrome. The most common clinical manifestations of gastrointestinal TB are abdominal pain, fever, weight loss, anorexia, nausea, vomiting, and diarrhea. 92 The nonspecificity of these findings as well as those on the physical examination may lead to the misdiagnosis of gastrointestinal TB as appendicitis, intestinal obstruction, or cancer. Approximately 12 to 16% of cases present as an acute abdomen. 92 The signs and symptoms can be so similar to those of other diseases that the diagnosis often is made at surgery. The clinical manifestations of anal TB include fissures, fistulas, and perirectal abscesses. 40 Antimicrobial treatment of gastrointestinal TB is the same as that of pulmonary disease. 68,92 Peritonitis Tuberculous peritonitis may develop from local spread of MTB infection from a tuberculous lymph node, intestinal focus, or infected fallopian tube. In addition, peritonitis can develop from seeding of the peritoneum in miliary TB or from the reactivation of a latent focus. 25 The patient with tuberculous peritonitis commonly has pain and abdominal swelling associated with fever, anorexia, and weight loss. Diagnosis may be confounded by the similarity of this disease to alcoholic hepatitis and by the fact that this disease often coexists with other disorders, especially cirrhosis with ascites. 40 Paracentesis is thus essential. The peritoneal fluid is exudative, with a cell count of 500 to 2000 cells per ml. Lymphocytes usually predominate, with rare exceptions early in the process, when polymorphonuclear leukocytes may predominate. 25 AFB smears of the fluid have a low diagnostic yield, with a reported sensitivity of no more than 7%, and the culture result is positive in only 25% of the cases. Peritoneal biopsy often is necessary to confirm the diagnosis. Treatment is the same as for pulmonary TB, with a 6-month regimen. 25,68 MANAGEMENT Initial Emergency Department Management The most emergent presentation of pulmonary TB is massive hemoptysis, defined as loss of at least 600 ml of blood in 24 hours. Exsanguination rarely occurs, and the major morbidity is due to asphyxiation from aspirated blood. The airway should be secured with a large-diameter (8-mm) endotracheal tube that can accommodate a fiberoptic bronchoscope. The patient should be positioned with the bleeding lung in a dependent position. Selective main bronchus intubation should be considered to allow ventilation of the unaffected lung and to minimize the spread of blood from the affected lung. Emergent consultation for bronchoscopy, surgical resection, or angiography with selective embolization is required. 49 Patients suspected of having active pulmonary TB should be immediately placed in respiratory isolation. Medical Therapy Patients suspected of having pulmonary TB whose sputum smears return positive for AFB can be presumptively diagnosed and treated with antituberculosis agents. In patients with negative findings on a sputum smear but clinical and radiographic findings consistent with pulmonary TB, it also may be appropriate to initiate treatment for presumptive TB. 68 A few days of therapy with antituberculosis agents does not interfere with bacteriologic diagnosis, so severely ill patients with presumed TB should be treated immediately. Local factors, including the prevalence of TB and available resources, help determine the appropriateness of presumptive therapy.