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 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.¹² 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 apical posterior areas of the lungs. These sites may be favored because of a high oxygen tension or impaired clearance mechanisms from poor lymph flow.

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. Cell-mediated immunity occurs through CD4⁺ helper T cells. 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.¹²

Delayed-type hypersensitivity is mediated by cytotoxic CD8⁺ suppressor T cells. The cytotoxic cells kill nonactivated macrophages laden with mycobacteria and thus cause local tissue destruction. 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. Tubercle bacilli can survive dormant in this solid caseous material for years.¹² The host’s resistance determines whether the disease remains dormant or becomes active.

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. Similarly, at sites of lymphohematogenous spread, the mycobacteria are quickly destroyed by a rapid immunologic response. The rapid destruction of the mycobacteria by cell-mediated 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.

This sequence of events from stage 1 to stage 3 represents the pathogenesis of primary TB in the immunocompetent patient. In most cases, primary TB is subclinical and self-limited. 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 manifestations 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. 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. 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.¹² 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 liquefied caseous material, teeming with mycobacteria, enters other parts of the lung and the outside environment. The spilling of this liquefied material within the lung may produce a caseous bronchopneumonia.¹² 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.¹²

History of Present Illness

Clinically significant pulmonary TB often is indolent, and signs and symptoms are absent or minimal until the disease advances. Systemic reaction, thought to be mediated by cytokines, especially tumor necrosis factor alpha, causes the constitutional symptoms of anorexia, weight loss, fatigue, irritability, malaise, weakness, headache, chills, and, most commonly, fever.14,17 The fever usually develops in the afternoon; defervescence occurs during sleep, leading to the classic night sweats of TB.¹⁴

Cough is the most common symptom of pulmonary TB. It may initially be nonproductive, but as caseation necrosis and liquefaction develop, mucopurulent and nonspecific sputum typically is produced.14,17 Hemoptysis, caused by caseous sloughing or endobronchial erosion, usually is minor but often indicates extensive lung involvement. 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. Shortness of breath from parenchymal lung involvement is unusual, however, and if present indicates extensive parenchymal disease or tracheobronchial obstruction.¹⁴ Table 135-1 shows the frequency of symptoms found in one study of patients with culture-proven pulmonary TB. The clinical manifestation of TB in patients presenting to the 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.¹⁸

Any vague systemic disorder or fever of unknown etiology may represent TB. Atypical presentations are particularly common in infants, elders, 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 may erode through the bronchial wall, causing symptomatic endobronchial disease and allowing endobronchial spread of tuberculous pneumonia to other areas of the lungs. By contrast, fewer elders present with respiratory symptoms. The diagnosis may be masked by coexistent disease and nonspecific presenting symptoms.¹⁹ Pulmonary TB should be considered in elderly patients with chronic cough and failure to thrive.⁵

Clinical manifestations of TB in patients coinfected 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 MTB and HIV leads to a greatly increased viral load. Active TB with HIV coinfection has been associated with an increased risk for opportunistic infections and death. Patients with advanced HIV infection also commonly have extrapulmonary involvement (seen in 30%) as well as combined pulmonary and extrapulmonary TB (in 32%).¹⁷

Risk Factors

All patients in the ED who have been coughing should be screened for the presence of TB risk factors (Box 135-1). One of the most important risk factors is HIV/AIDS with CD4⁺ levels below 500 cells/µL.²⁰ Overseas, coinfection with HIV and TB is common and results in increased mortality of TB. 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 do. 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, elders typically have disease manifestations similar to those in young children. 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 (Box 135-2). Household contacts also have increased risk of TB infection.²¹

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 with an appropriate regimen may signal nonadherence to therapy or the presence of a resistant strain.²²

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 (Fig. 135-1). Delayed tube thoracostomy and suction result in progressive infection and fibrosis of the pleura that leads to air trapping within affected lung.

Empyema

An empyema, characterized by extensive, progressive parenchymal disease and cavitation, may develop in patients with TB. Although it is 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.

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.

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 by tuberculous adenitis or lymphatic dissemination to the airway. Tuberculous bronchostenosis may appear radiographically as persistent segmental or lobar collapse, lobar hyperinflation, and obstructive pneumonia.

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.

Superinfection

Extensive TB infection often heals with open cavities and areas of bronchiectasis. Superinfection may occur with a wide variety of organisms, including Aspergillus fumigatus.¹⁴ The characteristic finding on chest radiographs is the aspergilloma or “fungus ball” (Fig. 135-2). Aspergillomas are of particular clinical significance because they may cause massive and fatal hemoptysis.¹⁴

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. An uncommon complication is the erosion of a tuberculous lesion or cavity into a pulmonary artery, leading to pseudoaneurysm formation (Rasmussen’s aneurysm), with potentially fatal hemoptysis. 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.²³

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.²⁴ In the United States, TB is the leading cause of pericarditis among HIV-infected patients. The predominant symptoms are cough, chest pain, and dyspnea, and the most common signs are cardiomegaly, audible rub, fever, and tachycardia.²⁵ Complications of pericardial TB include pericardial effusion, constrictive pericarditis, myocarditis, and cardiac tamponade.²⁴ 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.²⁶

Primary Tuberculosis

Chest radiographic manifestations of primary disease in adults often are not recognized as TB.²⁸ Primary tuberculous infiltrates can occur in any lobe. With any age group, a pneumonic infiltrate with enlarged hilar or mediastinal nodes should strongly suggest the diagnosis. 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 it is present, being the only distinguishing feature.

Lymphadenopathy is considered the radiologic hallmark of primary TB in children but is seen less commonly in adults. When it is present, adenopathy usually is unilateral and associated with parenchymal infiltrate (Fig. 135-3). It may occur bilaterally or, more rarely, may be an isolated finding on chest radiography.¹⁴ 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.

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 elders; and tuberculomas, well-circumscribed nodular lesions of the parenchyma thought to be a result of healed primary TB.²⁹ 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. A right-sided predominance in the distribution of Ghon foci and Ranke complexes is well recognized and probably reflects the higher statistical probability that an airborne infection will affect the right lung. Calcification seen on the chest radiograph indicates healing, but viable bacilli may still exist in a partially calcified lesion.

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. In some patients, the primary tuberculous pneumonia breaks down into multiple cavitary lesions or a single large abscess. 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.²⁹ Postprimary disease also occurs in the lower lung. In addition, bronchogenic spread can occur, leading to involvement of multiple lobes (Fig. 135-4). The patient with bilateral upper lobe disease is extremely likely to have TB. 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. 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. 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.

Fibroproductive lesions often are irregular and angular in contour, have strands extending toward the hilum, and demonstrate calcification of one or more nodules. 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. 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. Only serial radiographs can reliably differentiate active from inactive disease. Lack of radiographic changes during a 4- to 6-month interval generally indicates “inactive” or, more precisely, “radiographically stable” disease.

Cavitation should alert ED personnel to the potential 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. 135-4). Cavities usually are multiple and range in diameter from a few millimeters to several centimeters. The walls of the cavities initially are thick and rough and become thinner and smoother with healing (Fig. 135-5). A hazy, parenchymal reaction around a cavity with an ill-defined 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. Although pulmonary TB usually induces chest radiographic changes, patients with sputum cultures positive for MTB may nevertheless demonstrate normal radiographic findings. Chest radiographs also may be normal in appearance in patients with endobronchial TB.

Chest radiographs of patients with pulmonary TB and HIV infection may be atypical in approximately one third of cases. 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.³⁰ Severe immunosuppression has been reported to be associated with a miliary pattern of disease on chest radiographs. 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. A normal chest radiographic appearance also is common in patients with HIV infection.

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. Classically, three initial sputum specimens should be obtained on different days. A positive smear supports 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 collection of samples.³¹ 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.³¹ In children, sputum obtained by bronchoscopy has a lower culture yield, so this technique is used less often to obtain sputum from pediatric patients.³²

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 support a presumptive diagnosis of TB (Fig. 135-6), and results usually are available within 24 hours.³³ 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.^32,33 Negative findings on an AFB smear, however, do not rule out active pulmonary TB because microscopy is relatively insensitive when it is performed on samples with small numbers of bacilli. At least 5000 bacilli/mL of sputum must be present for a positive result by microscopy.³³ 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.⁴ Overall, AFB smears have a sensitivity of 20 to 80% and a specificity of 90 to 100%.³³ Despite its limitations, microscopy remains an essential diagnostic test because of its ease of performance, low cost, rapid turnaround time, and reasonable diagnostic yield.

Drug Susceptibility Testing

Because of the emergence of multidrug-resistant MTB, all initial isolates of MTB should be tested for susceptibility to isoniazid, rifampin, and ethambutol.³⁴ 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-resistant contact or source, or has demonstrated a positive result on sputum cultures beyond 3 months of therapy.³⁴ 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 results obtained in fewer than 12 days.³³ Other new approaches to susceptibility testing include flow cytometry, genotypic sequence-based methods, and bacteriophage viability testing.^33,35

QuantiFERON Test

The QuantiFERON test is the most widely available IFN-γ release assay available. This test was approved in 2001 by the U.S. Food and Drug Administration (FDA). It uses an enzyme-linked immunosorbent assay (ELISA) to measure the amount of IFN-γ released in response to PPD. 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 ranges from 90 to 100%. It can rapidly confirm TB infection in an individual in 2 days. This compares with several weeks for a traditional culture.³⁶ However, a normal study does not completely exclude TB; therefore, cultures should be sent when persons thought to have TB have a negative QuantiFERON test result.