INTRODUCTION — The lungs are the major site for Mycobacterium tuberculosis primary infection and tuberculosis (TB) disease. The clinical manifestations and evaluation of pulmonary TB will be reviewed here. The epidemiology, pathogenesis, diagnosis, and treatment of pulmonary TB are discussed separately, as are extrapulmonary and miliary TB. (See related topics.)
Natural history — The natural history of TB infection is described in detail separately. (See "Tuberculosis: Natural history, microbiology, and pathogenesis", section on 'Natural history of infection'.)
After primary infection, 90 percent of individuals with intact immunity control further replication of the bacilli, which may then be cleared or enter a "latent" phase. The person remains asymptomatic, but latent disease has the potential to become active at any time.
The remaining 10 percent of individuals develop progressive primary disease with TB pneumonia and expansion of infiltrates at the site of the initial seeding or near the hilum and may have hilar lymphadenopathy. Individuals with pulmonary involvement may also present with disease at more distant sites, commonly with cervical lymphadenopathy, meningitis, pericarditis, or miliary dissemination. Progression to local pulmonary disease or dissemination occurs more frequently in those with poor immune responses, such as in those with human immunodeficiency virus (HIV) infection, chronic kidney failure, poorly controlled diabetes mellitus, and in those receiving immunosuppressive medications (including transplant recipients), young children (before the age of five), and older adults.
Individuals with latent TB have bacilli that can "reactivate" and progress to symptomatic disease. Approximately two to three billion people in the world are latently infected with M. tuberculosis, and 5 to 15 percent of these people will suffer from reactivation of TB during their lifetime. Factors including HIV infection, organ transplantation, silicosis, tumor necrosis factor-alpha blockers, close contacts, and kidney dialysis contribute to a significantly increased TB reactivation risk.
Primary tuberculosis — Primary TB is a term that describes new TB infection or active disease in a previously naïve host. Primary TB was considered to be mainly a disease of childhood until the introduction of effective antituberculous treatment with isoniazid in the 1950s. Many studies since that time have shown an increased frequency in the acquisition of TB in adolescents and adults [2,3].
Asymptomatic primary infection — Individuals with asymptomatic primary infection have no symptoms or signs suggesting TB disease. Individuals at risk of new TB infection and individuals at increased risk of reactivation warrant testing and treatment for latent TB infection, as discussed separately. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)" and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection".)
Symptomatic primary disease
Symptoms and signs — The natural history of primary TB was well described in a prospective study of 517 new tuberculin converters living on the Faroe Islands off the coast of Norway from 1932 to 1946 . The study included 331 adults and 186 children; all were followed for more than five years. The clinical manifestations of primary TB varied substantially in this population, and symptoms and signs referable to the lungs were present in approximately one-third of patients. Fever was the most common symptom, occurring in 70 percent of 232 patients in whom fever was not a condition for enrollment in the study. The fever onset was generally gradual and low grade but could be as high as 39°C (102.2°F) and lasted for an average of 14 to 21 days. Fever resolved in 98 percent of patients by 10 weeks.
Fever was not usually accompanied by other symptoms, although approximately 25 percent of patients developed pleuritic or retrosternal pain. One-half of patients with pleuritic chest pain had evidence of a pleural effusion. Retrosternal and dull interscapular pain were ascribed to enlarged bronchial lymph nodes and sometimes worsened with swallowing. Rarer symptoms included fatigue, cough, arthralgia, and pharyngitis. (See "Tuberculous pleural effusion".)
Chest radiography — In primary pulmonary TB, the chest radiograph is often normal. Common radiographic changes include hilar and/or mediastinal lymphadenopathy (image 1), pleural effusion, and pulmonary consolidation. The consolidation in primary TB may be segmental or lobar, may involve any lobe, and is typically homogeneous (image 2) . In one series including 517 patents with recent skin test conversion, chest radiograph findings were notable for the following :
●Hilar lymphadenopathy was the most common finding, occurring in 65 percent of cases. Hilar changes were visible early as one week after skin test conversion, and within two months in all cases.
●Pleural effusions developed in approximately one-third of patients, typically within the first three to four months after infection but occasionally as late as one year.
●Pulmonary consolidation was observed in 27 percent of patients; in general, it resolved slowly, over months to years.
•Perihilar and right-sided consolidation was the most common, and ipsilateral hilar enlargement was the rule.
•Contralateral hilar changes sometimes were present; only 2 percent of patients had bilateral consolidation.
•Lower and upper lobe consolidation was observed in 33 and 13 percent of patients, respectively; 43 percent of adults with consolidation also had effusions.
•The areas of consolidation progressed within the first year after skin test conversion in 20 patients (15 percent of cases), reflecting progressive primary TB. The majority of these patients had progression of disease at the original site; four developed cavitation.
Other studies that provide insight into the clinical manifestations of TB have focused retrospectively upon patients with culture-proven TB [6-8]. In one series from Canada, 188 patients were assessed, all of whom were culture positive and had abnormal chest radiographs . Thirty patients (18 percent) were classified clinically as having primary TB. The most common finding was lymphadenopathy, most commonly unilateral hilar or hilar and mediastinal, present in 67 percent. Right middle lobe collapse may complicate the lymphadenopathy but usually resolves with therapy.
Several factors probably favor development of atelectasis of the right middle lobe (RML). The RML bronchus is more densely surrounded by lymph nodes, it has a relatively longer length and smaller internal caliber, and it has a sharper branching angle.
In this retrospective series, pleural effusions were present in 33 percent and were the sole abnormality in 23 percent of cases . Pulmonary parenchymal involvement was present in 63 percent of patients and the consolidation involved primarily the upper lobes. Two patients had cavitation and two others had evidence of endobronchial spread. In another study, pulmonary consolidation occurred in 17 of 34 patients (50 percent) and it involved the mid and lower regions of the lungs slightly more often than the upper lung zones .
Computed tomography — Computed tomography (CT) scan with contrast may demonstrate a number of findings [10,11]:
●Enlarged (>2 cm) lymph nodes; common features include low attenuation (reflecting caseous necrosis) as well as peripheral rim enhancement (image 2). Rarely, lymphadenopathy may cause bronchial compression and/or airway compromise
●Consolidation in primary TB is usually dense and homogeneous but may also be patchy, nodular, or mass like.
●Tracheobronchial stenoses, mediastinitis, and even mediastinal abscesses may be observed.
●Solitary cavities can occur in up to 10 percent of patients.
●Pleural effusions occur in about 10 percent of adults with primary TB; they are usually unilateral, on the same side as the primary focus.
●Rarer manifestations in adults include large masses and spontaneous pneumothorax.
Postprimary and reactivation tuberculosis
General principles — Postprimary TB may result from reactivation of remote infection or via new (exogenous) infection in a previously infected person. The terms postprimary and reactivation TB are often used interchangeably since they present with similar radiographic findings (regardless of pathogenesis) and can be distinguished clinically only by history and epidemiology.
Postprimary TB may remain undiagnosed and potentially infectious for two to three years or longer, with development of symptoms only late in the course of the disease. The symptoms of postprimary TB have been described retrospectively, mainly in case series of hospitalized patients in single institutions [12-14]. In these series, symptoms typically began insidiously and were present for weeks or months before the diagnosis was made. One-half to two-thirds of patients developed cough, weight loss, and fatigue. Fever and night sweats or night sweats alone were present in approximately one-half. Chest pain and dyspnea each were reported in approximately one-third of patients and hemoptysis in approximately one-quarter. Many patients had vague or nonspecific symptoms; almost one-third of patients had pulmonary TB diagnosed after an admission for unrelated complaints .
●Fever is usually low grade at onset but becomes marked with progression of disease. It is classically diurnal, with an afebrile period early in the morning and a gradually rising temperature throughout the day, reaching a peak in the late afternoon or evening. Fever subsides during sleep, but night sweats may occur. Fever and night sweats are more common among patients with advanced pulmonary TB .
●Cough may be absent or mild initially and may be nonproductive or productive of only scant sputum. Initially, it may be present only in the morning, when accumulated secretions during sleep are expectorated. As the disease progresses, cough becomes more continuous throughout the day and productive of yellow or yellow-green and occasionally blood-streaked sputum, which is rarely foul smelling. Symptomatic individuals are more likely to have smear-positive sputum . Frank hemoptysis, due to caseous sloughing or endobronchial erosion, typically occurs later in the disease and is rarely massive. Nocturnal coughing is associated with advanced disease, often with cavitation.
●Dyspnea can occur in the setting of extensive parenchymal involvement, pleural effusions, or a pneumothorax. Pleuritic chest pain is not common but, when present, signifies inflammation abutting or invading the pleura, with or without an effusion. Rarely, this can progress to frank empyema.
●In the absence of treatment, patients may present with painful ulcers of the mouth, tongue, larynx, or gastrointestinal tract due to chronic expectoration and swallowing of highly infectious secretions; these findings are rare in the setting of antituberculous therapy.
●Anorexia, wasting (consumption), and malaise are common features of advanced disease and may be the only presenting features in some patients.
Ambulatory patients with active TB typically have milder and less specific symptoms than hospitalized patients. In a study including 313 TB cases identified among ambulatory patients, cough >2 weeks was observed among 52 percent of patients with pulmonary disease; fever >2 weeks was observed among 29 percent of patients . In addition, clinical symptoms were observed less frequently among patients of Asian ethnicity than among other patients.
Other comorbidities may affect the presentation of TB reactivation; these include diabetes, administration of tumor necrosis factor (TNF)-alpha inhibitors and advanced HIV infection. Such patients present with more symptoms and a higher proportion of smear positivity, cavitation, treatment failure, and non-TB deaths . (See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors" and "Diagnosis of pulmonary tuberculosis in adults".)
Presentation in older adults — In nonendemic countries, the incidence of pulmonary TB is two to three times higher among older adults, especially those in old age homes, and the risk of death is higher compared with younger patients [19,20].
Comparative studies have suggested some differences in the manifestations of pulmonary TB between older and younger patients. A meta-analysis including 12 studies noted no significant differences between patients >60 years and patients <60 years with respect to time to diagnosis, prevalence of cough, sputum production, weight loss, or fatigue/malaise . Findings observed less commonly among older adults included fever, sweats, hemoptysis, cavitary disease, and a positive tuberculin skin test, but they were likely to present with the nonspecific symptoms of dyspnea and fatigue. Findings observed more frequently among older adults included hypoalbuminemia, leukopenia, and underlying disorders such as cardiovascular disease, chronic obstructive pulmonary disease (COPD), diabetes, malignancy, and gastrectomy. Cavitary disease is less common, and multilobar and lower lobe involvement more common. Because of comorbidities such as COPD and the nonspecificity of symptoms, the diagnosis in older adults can be delayed or missed [22,23].
Physical findings — Physical findings of pulmonary TB are not specific and usually are absent in mild or moderate disease. Dullness with decreased fremitus may indicate pleural thickening or effusion. Crackles may be present throughout inspiration or may be heard only after a short cough (posttussive crackles). When large areas of the lung are involved, signs of consolidation associated with open bronchi, such as whispered pectoriloquy or tubular breath sounds, may be heard. Distant hollow breath sounds over cavities are called amphoric, after the sound made by blowing across the mouth of jars used in antiquity (amphorae). Extrapulmonary signs include clubbing and findings localized to other sites of involvement. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis".)
Laboratory findings — The approach to diagnosis of TB is discussed separately. (See "Diagnosis of pulmonary tuberculosis in adults".)
Routine hematology and biochemistry laboratory studies are frequently normal in the setting of pulmonary TB. The C-reactive protein (CRP) can be elevated in up to 85 percent of patients . Late in the disease, hematologic changes may include normocytic anemia, leukocytosis, or, more rarely, monocytosis. Hyponatremia may be associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH)  or rarely with adrenal insufficiency. Hypoalbuminemia and hypergammaglobulinemia also can occur as late findings.
Radiographic findings — Most patients with postprimary TB have abnormalities on chest radiography, even in the absence of respiratory symptoms [12,26]. Postprimary TB typically involves the apical and posterior segments of the upper lobes (80 to 90 percent of patients (image 3)), followed in frequency by the superior segment of the lower lobes and the anterior segment of the upper lobes [12,27-29]. The most common and typical manifestation consists of patchy areas of consolidation with poorly defined margins [5,30]. In multiple large series of TB among adults, 70 to 87 percent had upper lobe consolidation typical of postprimary disease; 19 to 40 percent also had cavities, with visible air-fluid levels in as many as 20 percent of cases [12,27-29].
Adults without upper lobe consolidation or cavitation have "atypical" radiographic patterns (13 to 30 percent of pulmonary TB cases) [6,9,31]. These findings include hilar lymphadenopathy (sometimes associated with right middle lobe atelectasis), consolidation or cavities in the middle or lower lung zones, pleural effusions, and solitary nodules. These "atypical" findings are more common in the setting of primary TB and probably represent increasing incidence of primary TB rather than "atypical" forms of postprimary TB. (See 'Primary tuberculosis' above.)
Up to 5 percent of patients with active TB present with upper lobe fibrocalcific changes thought to be indicative of healed primary TB. However, such patients should be evaluated for active TB in the setting of pulmonary symptoms or absence of serial films documenting stability of the lesion.
A normal chest radiograph is also possible even in active pulmonary TB. As an example, in one Canadian study of 518 patients with culture-proven pulmonary TB, 25 patients (5 percent) had normal chest radiographs; 23 of these patients had pulmonary symptoms at the time of the normal radiograph . In this series conducted over a 10-year period, normal chest radiographs represented less than 1 percent of the radiographs in 1988 to 1989 but increased to 10 percent from 1996 to 1997.
CT scanning is more sensitive than chest radiography for diagnosis, particularly for smaller lesions located in the apex of the lung (image 3) . Chest CT is useful in patients with suspected pulmonary TB and normal or nonspecific abnormalities on chest radiograph. CT scans typically demonstrate more lesions than are visible on chest radiograph and are particularly helpful in detecting hilar or mediastinal lymphadenopathy.
Chest CT may also demonstrate apicoposterior consolidation, cavities, pleural effusions, fibrotic lesions causing distortion of lung parenchyma, elevation of fissures and hila, pleural thickening, and formation of traction bronchiectasis. High-resolution CT is the imaging technique of choice to detect early bronchogenic spread. The most common findings consist of centrilobular 2 to 4 mm nodules and branching linear or nodular opacities referred to as “tree-in-bud” pattern representing intrabronchiolar and peribronchiolar caseation necrosis .
Radiographic findings in the setting of pulmonary TB are discussed further separately. (See "Diagnosis of pulmonary tuberculosis in adults".)
Endobronchial tuberculosis — Endobronchial TB is defined as tuberculous disease that involves the tracheobronchial tree. It may develop via direct extension to the bronchi from an adjacent parenchymal focus (usually a cavity) or via spread of organisms to the bronchi via infected sputum. Lesions are more likely to be observed in the main and upper bronchi; in 5 percent of patients, the lower trachea is involved .
Prior to the availability of antituberculous therapy, endobronchial TB was relatively common in the setting of primary infection and postprimary TB [36-39]. In a 1943 study in a TB sanatorium in West Virginia, lesions in the tracheobronchial tree were observed in 15 percent of cases via rigid bronchoscopy and in 40 percent of cases at autopsy . Endobronchial disease was observed more frequently among patients with extensive pulmonary TB, particularly cavitary lesions. Upper lung parenchymal or cavitary disease with bronchogenic spread to the lower lobes was commonly observed, presumably from pooled infected secretions. Endobronchial TB appears to have a preponderance in females in their second and third decades of life [4,6] and in the older adult population (mean age 70 years) [7,40].
Since the availability of antituberculous therapy, endobronchial TB has been described in 6to 54 percent of patients with active pulmonary TB [41-44]. Some degree of bronchial stenosis is observed in 90 percent of cases of endobronchial TB; early diagnosis and prompt treatment prior to development of fibrosis are important to reduce the likelihood of this complication. Endobronchial disease in patients with primary infection has also been associated with impingement of enlarged lymph nodes on the bronchi [45-48]. Associated inflammation can lead to endobronchial ulceration or perforation. Other complications of endobronchial TB include obstruction, atelectasis (with or without secondary infection), bronchiectasis, and tracheal stenosis .
Symptoms — Symptoms include a productive cough, chest pain, hemoptysis, lethargy, fever, and dyspnea. Symptoms may be acute in onset and be confused with bacterial pneumonia, asthma , or foreign body aspiration . The clinical manifestations can also be subacute or chronic, resembling bronchogenic carcinoma .
A barking cough has been described in approximately two-thirds of patients with endobronchial disease, often accompanied by sputum production [47-49,52,53]. Rarely, patients develop so-called bronchorrhea, which is production of more than 500 mL/day of sputum . In some cases, caseous material from endobronchial lesions or calcific material from extension of calcific nodes into the bronchi is expectorated (known as lithoptysis). Wheezing and hemoptysis may also be observed. Lymph node rupture can be associated with chest pain. The presence of dyspnea may signal obstruction or atelectasis.
Physical findings — Physical findings can include diminished breath sounds, rhonchi, or wheezing. The wheeze typically is low pitched, monophonic, constant, and is auscultated consistently over the same area on the chest wall.
Radiographic findings — The most common radiographic finding of endobronchial spread of TB in adults is upper lobe consolidation and cavity with ipsilateral spread to the lower lobe and, less commonly, contralateral lung. This may result in multiple small nodules with or without areas of consolidation and cavitation. Endobronchial spread can exist without extensive parenchymal abnormalities.
On high-resolution CT, endobronchial spread of pulmonary TB, typically manifested by centrilobular nodules, has been reported as high as 95 and 97 percent in various studies (image 4) [33,55]. Another common manifestation of endobronchial spread on CT is the presence of branching linear structures originating from a single “stalk” with associated small centrilobular nodular opacities (the “tree-in-bud” appearance) (image 5).
Manifestations of extensive bronchial involvement on high-resolution CT include segmental bronchial narrowing with concentric wall thickening, complete endobronchial obstruction, extrinsic obstruction by adjacent lymphadenopathy with scarring, and, rarely, fistulas [5,56]. Extensive endobronchial TB can also be associated with bronchiectasis.
In patients with primary disease and endobronchial TB, segmental atelectasis may be the only finding; atelectasis is more frequent in the right middle lobe and the anterior segment of the right upper lobe.
Evaluation and approach — The diagnosis of endobronchial TB may be suspected based on the history and physical findings and chest radiography. Even with a highly suggestive high-resolution CT, the diagnosis should be confirmed by bronchoscopy with histopathology and microbiologic sampling.
Findings on bronchoscopy may include edematous-hyperemic lesions (with or without ulceration or fibrosis) or nonspecific bronchitis . Hilar node rupture may be visible as a mass protruding into the bronchial lumen; with perforation of the node into the bronchus, caseous or calcific material may be seen extruding into the lumen. Bronchial stenosis also may be visible [49,57]. The tendency to develop bronchial stenosis can be predicted from bronchoscopic appearances of the mucosa. Edematous-hyperemic, fibrostenotic, and tumorous lesions tend to progress to eventual bronchial stenosis and/or obstruction within three months even with appropriate antituberculous therapy.
Brushings of the lesions or lavage of the distal airways can increase the frequency of positive smears; the yield for cultures of this material is >90 percent [35,41]. (See "Diagnosis of pulmonary tuberculosis in adults".)
Complications — Bronchial stenosis and stricture formation may develop in more than two-thirds of patients, despite appropriate antituberculous therapy. Severe airway obstruction may develop if the larger airways are involved. Postobstructive bronchiectasis is another complication that leads to frequent pneumonia and hemoptysis. Some patients also developed persistent obstructive airway disease.
Management of pulmonary TB with complications is discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection", section on 'Pulmonary TB with complications'.)
Lower lung tuberculosis — In postprimary TB, the upper lobes are the most common site of disease. Sometimes only the lower lobes are affected; this can lead to misdiagnosis as viral or bacterial pneumonia, bronchiectasis, or carcinoma.
Lower lung TB refers to disease involvement below the hila (including the perihilar regions) on chest imaging . The incidence in adults is 2 to 9 percent [12,58]. Consolidation in lower lung TB tends to be more extensive and homogeneous than upper lobe TB [59-61]. Cavitation may occur, and large cavities have been described. Symptoms in lower lobe TB are generally either subacute in onset (mean of 12 weeks) or chronic (up to 6 months).
Lower lobe involvement can be a manifestation of primary TB (with involvement of adjacent lymph nodes), postprimary TB (involving the superior segments of the lower lobes), or endobronchial TB [59,60,62]. Endobronchial TB can affect the lower lung in both primary infection (especially when adjacent lymph nodes are involved) and postprimary disease (spread from upper lobe disease can secondarily infect the lower lobes) (image 4).
Older adult patients and those with HIV, diabetes, renal or hepatic disease, those receiving corticosteroids, and those with underlying silicosis appear at highest risk for lower lobe TB. However, many patients have no underlying medical illnesses. Studies in nursing homes suggest that lower lobe TB may be a manifestation of active TB in an older, tuberculin-negative population with significant underlying diseases or anergy . In some cases, the patients are suspected or known to have had previous TB but develop exogenous reinfection, perhaps due to a loss of demonstrable tissue hypersensitivity.
Tuberculoma — A pulmonary tuberculoma is a well-circumscribed nodule or a mass. It consists of caseous material encapsulated by multiple concentric layers of connective tissue without surrounding inflammation or spread. Pulmonary tuberculomas can occur in both primary and postprimary TB and have been described in 6 to 9 percent of reactivation TB . The proposed mechanism underlying the development of tuberculomas consists of repeated extension of bronchopneumonic foci, subsequent necrosis, and re-encapsulation. Other proposed mechanisms include shrinkage of occluded cavities and fusion of small encapsulated densities .
They are usually found in the upper lobes. A tuberculoma is one of the most common benign nodules and represents 5 to 24 percent of resected solitary pulmonary nodules . They are usually a single nodule; multiple nodules can occur. The size ranges from <1 cm to >10 cm in diameter. The margins are usually smooth and sharp but may be irregular (image 6); uncommonly, cavitation or calcification may be observed.
The natural history of tuberculomas without antituberculous therapy has been classified into progressive, stationary, and regressive; a stationary course accounts for 30 to 50 percent of all patients. In one series including 45 patients, symptoms were present in nearly half of cases; the most frequent symptoms were sputum, cough, general weakness, and fatigue .
The diagnosis of tuberculoma can be difficult since airway cultures are often negative . Fine needle aspiration or lung biopsy may be necessary for diagnosis. Tuberculomas may be accompanied by malignancy in rare cases. (See "Diagnostic evaluation of the incidental pulmonary nodule".)
The majority of pulmonary tuberculomas are reduced in size by antituberculous treatment and this tendency may continue after completing treatment. In the early phase of treatment, a tuberculoma may increase in size and may require careful observation or re-evaluation with further biopsies or resection .
Laryngeal tuberculosis — Laryngeal TB is divided into two forms based upon its pathogenesis: primary disease, which develops via direct invasion of bacilli into the larynx, and secondary disease, which develops via bronchogenic spread from advanced pulmonary TB or via hematogenous or lymphatic spread . The most common sites of involvement include the true vocal cords, epiglottis, and false vocal cords. On laryngoscopy, areas of hyperemia, nodules, ulcerations, or exophytic masses can be seen.
Middle-aged males are four times more likely to be affected than females . In one series including 127 US cases between 1970 and 2012, the mean duration of symptoms was 19 weeks (range 1 to 104 weeks) and mean age was 40.5 years . The most common symptoms were dysphonia (96 percent), weight loss (46 percent), cough (38 percent), dysphagia (26 percent), odynophagia (25 percent), and stridor (9 percent). Radiographic evidence of pulmonary TB was reported in 86 percent of cases; however, laryngeal TB can occur in the absence of pulmonary disease.
In another series including 36 Brazilian patients with laryngeal TB, the main presenting symptoms were dysphagia and cough; the true vocal folds the most frequently affected site . Smoking was associated with the development of more extensive lesions.
Laryngeal TB may be complicated by vocal cord paralysis. This can occur as a result of enlarged mediastinal lymph nodes compressing the recurrent laryngeal nerve along the intrathoracic course/aortopulmonary window or via stretching or entrapment of the recurrent laryngeal nerve due to mediastinal or lung fibrosis . Stenosis is the most common complication despite adequate treatment.
CT and magnetic resonance imaging better demonstrate the involvement of the surrounding structures and tissues of the larynx than laryngoscopy. Biopsy of the primary growth is diagnostic and may show caseating granulomatous inflammation. Microbiologic confirmation is generally low yield.
Prior to the availability of antituberculous therapy, laryngeal TB was considered a terminal condition, as it usually occurred during progression of pulmonary disease, developing soon before death. Since the availability of antituberculous therapy, laryngeal TB has become relatively rare (<1 percent of United States TB cases). Surgery is reserved for cases of airway compromise.
Patients with HIV infection
General principles — The clinical manifestations of TB in patients with HIV infection are influenced by the degree of immunosuppression [71,72]. Early in the course of HIV disease, the clinical presentation of TB is similar to that of HIV-uninfected patients; symptoms include fever, cough, weight loss, fatigue, loss of appetite, night sweats, and hemoptysis. Patients with HIV and diabetes are 31 times more likely to have active TB if hemoptysis was a presenting symptom .
As immunity declines, the frequency of pulmonary cavitation and hemoptysis also declines [71,72]. HIV-infected patients with advanced immunosuppression are at increased risk of extrapulmonary TB and disseminated TB [74-79]. Virtually any site can be involved; the most common presentations are lymphadenitis and pleural involvement [72,74,79-83]. Septicemic-like illness with hypotension can occur, with high mortality rate unless diagnosed and treated rapidly. In contrast, active TB may be subclinical in some patients with advanced immunosuppression, with no symptoms and a normal chest radiograph . (See "Tuberculous lymphadenitis" and "Tuberculous pleural effusion".)
Effect of antiretroviral therapy — In patients who develop active TB while on antiretroviral therapy (ART), the clinical presentation depends on the level of immunosuppression. In one study from South Africa, the World Health Organization symptom screen (presence of any: active cough of any duration, fever, night sweats, or weight loss) had lower sensitivity among patients on ART than among patients not on ART (24 vs 47 percent), but higher specificity (94 vs 80 percent) .
Immune reconstitution inflammatory syndrome (IRIS) is an inflammatory disorder that can occur in association with initiation of ART in some HIV-infected individuals; it is typically associated with paradoxical worsening of pre-existing infectious processes, including TB. Issues related to IRIS are discussed separately. (See "Immune reconstitution inflammatory syndrome", section on 'Tuberculosis'.)
Radiographic findings — Early in the course of HIV disease, radiographic findings of TB are similar to that of HIV-uninfected patients, as described in the preceding sections. (See 'Radiographic findings' above and 'Radiographic findings' above.)
As immunity declines (eg, in patients not treated with ART), radiographic findings are more likely to be atypical, including noncavitary pulmonary consolidation with no particular preference for the upper lobes (image 7 and image 8) [71,72]. HIV-infected patients with CD4 count <200 cells/mm3 are more likely to have mediastinal or hilar lymphadenopathy and extrapulmonary involvement and are less likely to have cavitation (compared with HIV-infected patients with CD4 count ≥200 cells/mm3). Miliary or disseminated disease has also been associated with severe immunosuppression .
In one study including 133 patients with HIV/acquired immunodeficiency syndrome (AIDS) and TB in New York City prior to the availability of ART, chest radiograph findings were as follows :
●Pattern typical for primary TB: 36 percent. These findings included pleural effusion, intrathoracic lymphadenopathy (mediastinum and hilum), or middle or lower lobe consolidation without cavitation.
●Pattern compatible with postprimary TB: 29 percent. These findings included apical/posterior consolidation of the upper lobes or consolidation of the superior segments of the lower lobes (without adenopathy or effusion), endobronchial spread (acinar or 3 to 4 mm shadows, remote from a cavity or upper lobe consolidation), or bronchiectasis.
●Miliary pattern: 4 percent.
●Atypical findings for TB, such as diffuse infiltrates: 13 percent.
●Minimal changes: 5 percent.
●Normal chest radiographs: 14 percent.
Most patients with CD4 count ≥200 cells/mm3 had typical patterns of postprimary disease (ie, cavitation and upper lobe consolidation), while patients with CD4 count <200 cells/mm3 were nearly as likely to have normal chest radiographs as they were to have patterns of reactivation disease (21 versus 23 percent). A number of other studies have also reported that normal chest radiographs are common in patients with CD4 counts <200 cells/mm3 [74,86-89].
Similarly, in a study from South India including 200 HIV-infected patients with CD4 <200 cells/mm3, noncavitary infiltration and consolidation was the predominant finding . Radiographic findings consisted of diffuse or mid and lower lung zone involvement, rather than classic upper lobe involvement. With restoration of cellular immunity on ART, radiographic findings are more likely to resemble those in patients with CD4 counts >200 cells/mm3.
Chest CT is useful in patients with suspected pulmonary TB and normal or nonspecific abnormalities on chest radiograph. Even if there is no parenchymal disease, lymphadenopathy or pleural effusions may be observed.
COMPLICATIONS — Pulmonary complications of TB include hemoptysis, pneumothorax, bronchiectasis, extensive pulmonary destruction (including pulmonary gangrene), fistula, tracheobronchial stenosis, malignancy, and chronic pulmonary aspergillosis. These complications occur more commonly in the setting of postprimary disease.
Tuberculous effusions and empyema are discussed separately (See "Tuberculous pleural effusion".)
Hemoptysis — Hemoptysis occurs most frequently in the setting of active TB but may also occur after completion of treatment [91-93]. Approximately 8 percent of patients with pulmonary TB infection experience hemoptysis at some point . Many patients with hemoptysis are acid-fast bacilli (AFB) smear positive and usually have cavitary disease. Bleeding usually is of small volume, appearing as blood-streaked sputum. Massive hemoptysis is a rare complication since the advent of antituberculous therapy. Prior to effective treatment, massive hemoptysis accounted for approximately 5 percent of deaths from TB. In a South African case series, up to 73 percent of massive hemoptysis was attributable to active TB .
Sources of massive hemoptysis due to TB include the pulmonary artery, bronchial arteries, intercostal arteries, and other vessels supplying the lung. Tuberculous vascular lesions include pulmonary or bronchial arteritis and thrombosis, bronchial artery dilatation, and Rasmussen aneurysm. "Rasmussen's aneurysm" is a relatively uncommon cause of hemoptysis; it refers to the formation of an aneurysm in the setting of cavitary infection that extends into the adventitia and media of bronchial arteries, resulting in inflammation and thinning of the vessel wall [96,97]. This aneurysm subsequently ruptures into the cavity, producing massive hemoptysis.
Hemoptysis after the completion of therapy for TB only occasionally represents TB recurrence. Other causes include residual bronchiectasis, an aspergilloma or other fungus ball invading or colonizing an old healed cavity, a ruptured broncholith that erodes through a bronchial artery, a carcinoma, or another infectious or inflammatory process.
Patients with significant hemoptysis should be evaluated promptly to define the source of bleeding and to facilitate immediate intervention. Apart from impending exsanguination (which requires immediate surgical care), bronchial artery embolization is the preferred management approach if feasible [98,99]. In one study including 140 patients with TB and massive hemoptysis (more than 300 mL of blood in 24 hours) who underwent bronchial artery embolization, nearly complete control of hemoptysis was achieved in 73 percent of cases . In the absence of access to appropriate facilities for bronchial artery embolization, other treatments includes bed rest, postural management, volume replacement, cough suppression, and intravenous vasopressin . (See "Evaluation and management of life-threatening hemoptysis".)
If embolization and medical management fail, surgical options include ligation of arteries, resection of a lung lobe, and endobronchial tamponade. Both ligation and embolization can be complex because of the frequent presence of multiple feeder arteries often connecting systemic with bronchial circulation . Elective resection is associated with a mortality of 18 percent, and emergency lung resection for life-threatening hemoptysis a mortality up to 40 percent . Older studies suggest that after an episode of massive hemoptysis or repeated episodes of severe hemoptysis, surgical intervention improves survival [103-105] and should be considered if embolization fails.
Pneumothorax — Prior to the availability of antituberculous therapy, spontaneous pneumothorax was a frequent and dangerous complication of pulmonary TB . Since the availability of antituberculous therapy, spontaneous pneumothorax associated with TB has been reported in about 1 percent of hospitalized patients [107-109]. A case series from Turkey reported pneumothorax in 1.5 percent of cases of pulmonary TB . In regions where TB is endemic, it may be the most common cause of spontaneous pneumothorax .
Pneumothorax appears to result from the rupture of a peripheral cavity or a subpleural caseous focus with liquefaction into the pleural space [107,108]. Inflammation can lead to development of a bronchopleural fistula, which can persist or seal off spontaneously. The lung may reexpand if the bronchopleural fistula seals spontaneously, but more commonly chest tube drainage is required.
Factors preventing successful chest tube drainage and expansion include extensive pulmonary parenchymal disease with large fistulas, a long interval between pneumothorax and chest tube insertion, and the development of an empyema due to TB and/or bacterial superinfection. However, successful closure of even extensive air leaks has been reported after as much as six weeks of chest tube drainage accompanied by appropriate antituberculous therapy . (See "Treatment of secondary spontaneous pneumothorax in adults".)
Bronchiectasis — Bronchiectasis may develop following primary or postprimary TB and can be associated with hemoptysis [112-117]. (See "Clinical manifestations and diagnosis of bronchiectasis in adults".)
Following primary TB infection, extrinsic compression of a bronchus by enlarged nodes may cause bronchial dilation distal to the obstruction. There may be no evidence of parenchymal TB.
In the setting of postprimary TB, progressive destruction and fibrosis of lung parenchyma may lead to localized bronchial dilation. If endobronchial disease is present, bronchial stenosis may result in distal bronchiectasis. Bronchiectasis is more frequent in the common sites of postprimary TB (apical and posterior segments of the upper lobe) but may be found in other areas of the lung.
Broncholithiasis — Broncholithiasis is defined as the presence of calcified or ossified material within the lumen of the tracheobronchial tree; it is an uncommon complication of pulmonary TB. The calcific nidus in a tuberculous lymph node erodes into the bronchial wall and may occlude the bronchus . Presenting symptoms may include cough, hemoptysis, wheezing, or evidence of recurrent pneumonia .
Extensive pulmonary destruction — Rarely, untreated or inadequately treated TB can cause progressive, extensive destruction of areas of one or both lungs [119,120]. In primary TB, occasionally lymph node obstruction of the bronchi together with distal collapse, necrosis, and bacterial superinfection can produce parenchymal destruction . More commonly, destruction results from chronic postprimary TB, typically in the absence of effective antituberculous therapy. Symptoms include progressive dyspnea, hemoptysis, and weight loss.
Pulmonary gangrene refers to acute pulmonary destruction which occurs as a rare complication of severe pulmonary infection. It has been described most frequently in the setting of pulmonary infection due to Klebsiella pneumonia or Streptococcus pneumonia; pulmonary gangrene due to TB has also been described [121,122]. Pulmonary gangrene occurs as a consequence of arteritis and thrombosis of distal pulmonary vessels, leading to an inflammatory pyogenic process and massive necrosis of lung parenchyma.
This form of TB progresses rapidly from a homogeneous, extensive infiltrate to dense consolidation. Air-filled cysts develop and coalesce into cavities. Necrotic lung tissue attached to the wall of the cavity may be observed. Pulmonary gangrene may resemble an intracavitary clot, fungus ball, or Rasmussen's aneurysm. The presence of a mobile mass that contains pulmonary tissue within a pulmonary cavity is characteristic on computed tomography scanning.
Resolution with effective antimicrobial therapy has been described . In many cases, urgent surgical intervention is needed because of life-threatening complications such as acute respiratory failure and shock that persist despite appropriate antimicrobial therapy .
Mortality usually is high; in one series including four patients, three died . In another series including 18 patients with extensive destruction of one or both lungs, eight died . Causes of death were massive hemoptysis and respiratory failure, sometimes in the presence of active TB or superinfection. Radiographically, patients had large cavities and fibrosis of remaining lung; in some cases, air-fluid levels at the base of the destroyed lung were observed [119,120].
Respiratory failure — Acute respiratory distress syndrome (ARDS) requiring mechanical ventilation as a presentation of TB is rarely reported. Mortality rates range between 47 and 80 percent. Patients with miliary or disseminated TB were significantly more likely to develop respiratory failure requiring mechanical ventilation despite the availability of effective antituberculous therapy .
Septic shock — TB can cause septic shock; the manifestations are similar to bacterial septic shock. Compared with patients with septic shock due to other pathogens, patients with septic shock due to TB have lower mean body mass indices (22 versus 27), lower mean white blood counts (10.4 versus 16.2), and are more often HIV infected (15 versus 3 percent) . The probability of survival in patients with M. tuberculosis septic shock is extremely poor, with an in hospital mortality rate of 79 percent; delayed initiation of appropriate therapy likely played an important role in clinical outcome . Extrapulmonary disease may be observed in more than 50 percent of cases. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)
Malignancy — A study conducted by the National Cancer Institute found that pulmonary TB was associated with an increased risk of lung cancer, after adjustment for active smoking and socioeconomic status (odds ratio 2.1, 95% CI 1.4-3.1) . Similarly, in a meta-analysis from China, TB was associated with a 1.78-fold increase in the risk of lung cancer among nonsmokers and an association with adenocarcinoma (relative risk 1.6; 95% CI 1.2-2.1) .
TB is thought to increase lung cancer risk via chronic pulmonary inflammation and fibrosis, but no causal relationship has been established. TB infection may cause a profound and extended host immune response, with inflammatory cells in the lung producing extensive cytokine signaling cascades, reactive nitrogen and oxygen species, prostaglandins, and tissue-destructive proteases. Mycobacterial cell wall components may induce production of nitric oxide and reactive oxygen species, which have been implicated in deoxyribonucleic acid (DNA) damage leading to carcinogenesis . Chronic inflammation may also enhance mutagenesis. In addition, immunosuppression and radiation therapy administered for treatment of lung cancer may be associated with an increased risk of TB.
Venous thromboembolism — TB, both pulmonary and extrapulmonary, has been suggested as an independent risk factor for venous thromboembolism (VTE), perhaps due to a hypercoagulable state. In a systematic review and meta-analysis including more than 16,000 patients with active TB, the prevalence of VTE was 3.5 percent, the prevalence of pulmonary embolism was 5.8 percent and the prevalence of deep vein thrombosis was 1.3 percent. Patients with active TB had a higher risk for VTE (odds ratio [OR] 2.90, 95% CI 2.30-3.67), DVT (OR 1.56, 95% CI 1.14-2.14), and PE (OR 3.58, 95% CI 2.54-5.05) .
The clinical approach to VTE is discussed further separately. (See "Overview of acute pulmonary embolism in adults".)
Chronic pulmonary aspergillosis — Chronic pulmonary aspergillosis can be a sequela of pulmonary TB, especially in those with cavitary disease. This is discussed further separately. (See "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis", section on 'Epidemiology and risk factors'.)
DIFFERENTIAL DIAGNOSIS — The following conditions can cause cavitary pulmonary lesions and symptoms suggestive of TB including fever, cough, and weight loss:
●Nontuberculous mycobacterial infection (NTM) – Symptoms of NTM include fatigue, dyspnea, and occasional hemoptysis; fever and weight loss occur less frequently than in patients with TB. Clinical features of Mycobacterium kansasii are often very similar to those of TB. NTM is distinguished from TB by culture results and/or molecular diagnostic testing. (See "Overview of nontuberculous mycobacterial infections".)
●Fungal infection – Fungal pneumonia can present with a range of manifestations including pneumonia, pulmonary nodule, and cavitary lung disease. It is distinguished from TB by epidemiologic exposure and culture results. (See "Diagnosis and treatment of pulmonary histoplasmosis" and "Diagnosis of invasive aspergillosis" and "Mucormycosis (zygomycosis)" and "Clinical manifestations and diagnosis of blastomycosis" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV".)
●Sarcoidosis – Sarcoidosis most commonly presents with diffuse interstitial lung disease. It rarely forms cavities and is distinguished from TB by histopathologic detection of noncaseating granulomas. (See "Clinical manifestations and diagnosis of sarcoidosis".)
●Melioidosis – Melioidosis is an infection caused by the bacterium Burkholderia pseudomallei. It can present with chronic cough, purulent sputum production, hemoptysis, and night sweats. In addition, imaging findings can mimic TB with cavitating, nodular, or streaky infiltrates with fibrotic changes. Uncommonly, infection can be latent and subsequently activate, as with TB. (See "Melioidosis: Epidemiology, clinical manifestations, and diagnosis".)
●Lung abscess – Lung abscess generally presents with fever, cough, and sputum production but without shaking chills or true rigors. Chest imaging usually shows infiltrates with a cavity. The diagnosis is established based on culture results. (See "Lung abscess in adults".)
●Septic emboli – Septic emboli to the lung from an extrapulmonary nidus are distinguished from TB by blood culture results and echocardiography. (See "Complications and outcome of infective endocarditis", section on 'Septic embolization'.)
●Lung cancer – Lung cancer most commonly presents with cough, hemoptysis, chest pain, and dyspnea. It is distinguished from TB by histopathology. (See "Clinical manifestations of lung cancer".)
●Lymphoma – Lymphoma typically presents with a rapidly growing mass together with fever, night sweats, and weight loss. It is distinguished from TB by histopathology. (See related topics.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hemoptysis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Tuberculosis (The Basics)")
●Beyond the Basics topic (see "Patient education: Tuberculosis (Beyond the Basics)")
●Disease forms − Clinical manifestations of pulmonary tuberculosis (TB) include postprimary TB, reactivation TB, endobronchial TB, lower lung field TB, and tuberculoma. (See 'Introduction' above.)
●Primary TB − Among patients with primary TB, clinical manifestations have been observed in approximately one-third of cases. Symptoms include fever and chest pain. Retrosternal pain and dull interscapular pain have been ascribed to enlarged bronchial lymph nodes. The physical exam is generally normal. The most common chest radiograph abnormality in one large series was hilar lymphadenopathy. Other manifestations include pleural effusions and pulmonary infiltrates. (See 'Primary tuberculosis' above.)
●Reactivation TB − Reactivation TB refers to reactivation of a previously dormant focus seeded at the time of the primary infection. The apical posterior segments of the lung are frequently involved (image 9). Typically, symptoms are insidious and may include cough, weight loss, fatigue, fever, night sweats, chest pain, dyspnea, and/or hemoptysis; these findings are observed less frequently among patients >60 years. Exogenous reinfection in a previously infected person may present with similar findings. (See 'Postprimary and reactivation tuberculosis' above.)
●Endobronchial TB − Endobronchial TB may develop via direct extension to the bronchi from an adjacent parenchymal focus (usually a cavity) or via spread of organisms to the bronchi via infected sputum. It can occur in patients with primary TB or postprimary TB and was observed more frequently prior to the antituberculous therapy era. Symptoms may be acute or chronic; a barking cough has been described in approximately two-thirds of patients. (See 'Endobronchial tuberculosis' above.)
●Patients with HIV infection − The clinical manifestations of TB in patients with HIV infection are influenced by the degree of immunosuppression. As immunity declines, extrapulmonary TB and disseminated TB are more common. Immune reconstitution inflammatory syndrome can occur with initiation of antiretroviral therapy in some individuals living with HIV and is associated with paradoxic worsening of TB. (See 'Patients with HIV infection' above.)
●Pulmonary complications − Pulmonary complications of TB include hemoptysis, pneumothorax, bronchiectasis, extensive pulmonary destruction (including pulmonary gangrene), acute respiratory distress syndrome, septic shock, malignancy, venous thromboembolism, and chronic pulmonary aspergillosis. (See 'Complications' above.)
●Differential diagnosis − The differential diagnosis for pulmonary TB is broad and includes other causes of chronic infection, inflammatory diseases, and malignancy. (See 'Differential diagnosis' above.)
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