Clinical manifestations of pulmonary tuberculosis pot

UptodateTuberculosis
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Clinical manifestations of pulmonary tuberculosis
Author
Nesli Basgoz, MD
Section Editor
C Fordham von Reyn, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Last literature review version 18.2: mayo 2010 | This topic last updated: febrero 22, 2005
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INTRODUCTION — The lungs are the major site for Mycobacterium tuberculosis
infection. Pulmonary manifestations of tuberculosis (TB) include primary, reactivation,
endobronchial, and lower lung field infection. Complications of TB can also involve the
lung, including hemoptysis, pneumothorax, bronchiectasis and, in some cases, extensive
pulmonary destruction.
The clinical manifestations of pulmonary TB will be reviewed here. The epidemiology,
pathogenesis and treatment of this infection are discussed separately. (See related topics).
PRIMARY TUBERCULOSIS — Primary tuberculosis was considered to be mainly a
disease of childhood until the introduction of effective chemotherapy with isoniazid in the
1950s. Many studies since that time have shown an increased frequency in the acquisition
of TB in adolescents and adults [1].
Symptoms and signs — The natural history of primary TB was best described in a
prospective study of 517 new tuberculin converters living on the Faroe Islands off the coast
of Norway from 1932 to 1946 [2]. This study included 331 adults and 186 children, all
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 only 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. Fever was generally low grade but could be as high as 39ºC and lasted for an
average of 14 to 21 days. All fever had resolved in 98 percent of patients by 10 weeks.

Symptoms in addition to fever were present only in approximately 25 percent of patients.
Chest pain and pleuritic chest pain were most common. One-half of patients with pleuritic
chest pain had evidence of a pleural effusion. (See "Tuberculous pleural effusions in HIV
seronegative patients" and "Tuberculous pleural effusions in HIV seropositive patients".)
Retrosternal and interscapular dull pain, sometimes worsened by swallowing, was ascribed
to enlarged bronchial lymph nodes. Rarer symptoms were fatigue, cough, arthralgias and
pharyngitis. The physical examination was usually normal; pulmonary signs included pain
to palpation and signs of an effusion.
Radiographic abnormalities — The most common abnormality on chest radiography was
hilar adenopathy, occurring in 65 percent [2]. Hilar changes could be seen as early as one
week after skin test conversion and within two months in all cases. These radiographic
findings resolved slowly, often over a period of more than one year.
Approximately one-third of the 517 converters developed pleural effusions, typically within
the first three to four months after infection, but occasionally as late as one year. Pulmonary
infiltrates were documented in 27 percent of patients. Perihilar and right sided infiltrates
were the most common, and ipsilateral hilar enlargement was the rule. While contralateral
hilar changes sometimes were present, only 2 percent of patients had bilateral infiltrates.
Lower and upper lobe infiltrates were observed in 33 and 13 percent of adults, respectively;
43 percent of adults with infiltrates also had effusions. Most infiltrates resolved over
months to years. However, in 20 patients (15 percent), the infiltrates progressed within the
first year after skin test conversion, so-called progressive primary TB. The majority of
these patients had progression of disease at the original site, and four developed cavitation.
Other studies, which provide insight into the clinical manifestations of TB, have focused
retrospectively upon patients with culture-proven TB [3-5]. In one series from Canada, 188
patients were assessed, all of whom were culture positive and had abnormal chest
radiographs [4]. Thirty patients (18 percent) were classified clinically as having primary
TB. The most common finding was hilar lymphadenopathy, present in 67 percent. Right
middle lobe collapse may complicate the adenopathy.
Several factors probably favor involvement of the right middle lobe:
 It is more densely surrounded by lymph nodes.

 It has a relatively longer length and smaller internal caliber.
 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 [4]. Pulmonary infiltrates were present in 63 percent of patients;
two patients had cavitation and two others evidence of endobronchial spread.
REACTIVATION TUBERCULOSIS — Multiple terms have been used to describe this
stage of TB: chronic TB, postprimary disease, recrudescent TB, endogenous reinfection,
and adult type progressive TB. Reactivation TB represents 90 percent of adult cases in the
non-HIV-infected population, and results from reactivation of a previously dormant focus
seeded at the time of the primary infection. The apical posterior segments of the lung are
frequently involved. The original site of spread may have been previously visible as a small
scar called a Simon focus.
Symptoms — The symptoms of reactivation TB have been described mainly in case series
of hospitalized patients in single institutions [6-8]. 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 non-specific symptoms; almost
one-third of patients had pulmonary TB diagnosed after an admission for unrelated
complaints [6].
The cough of TB may be mild initially and may be non-productive or productive of only
scant sputum. Initially, it may be present only in the morning, when accumulated secretions
are expectorated. As the disease progresses, cough becomes more continuous and
productive of yellow or yellow-green sputum, which is rarely foul-smelling. Frank
hemoptysis, due to caseous sloughing or endobronchial erosion, typically is present later in
the disease and is rarely massive.
Dyspnea can occur when patients have 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. This

rarely progresses to frank empyema. Although distinctly rare in the post-chemotherapy era,
patients may present with painful ulcers of the mouth, tongue, larynx or GI tract which are
caused by chronic expectoration and swallowing of highly infectious secretions.
Presentation in the elderly — Many comparative studies have suggested that pulmonary TB
differs in elderly patients compared to younger ones, including a longer duration of
symptoms before diagnosis and a lower frequency of pulmonary and constitutional
symptoms. When 12 of these studies were subjected to a meta-analysis, the time to
diagnosis, prevalence of cough, sputum production, weight loss or fatigue/malaise did not
differ significantly between patients older or younger than 60 years [9]. However, fever,
sweats and hemoptysis were less common in the elderly, and these patients were less likely
to have cavitary disease or a positive purified protein derivative (PPD) skin test. Elderly
patients also more commonly had hypoalbuminemia, leukopenia and underlying disorders,
such as cardiovascular disease, COPD, diabetes, malignancy, and gastrectomy.
Given the biases inherent in series based upon hospitalized patients, a population-based
study used questionnaires to study the clinical presentation of TB in prospectively
identified confirmed cases among ambulatory patients in Los Angeles county [10]. The
surveyed population of 313 out of a targeted 536 patients (58 percent) was predominantly
foreign-born (71 percent); 12 percent were HIV-infected. When normalized to account for
the HIV-infected patients, fewer patients had cough (48 percent), fever (29 percent), or
symptoms for more than two weeks than in previously published studies. When
demographic and clinical features associated with the presence of significant symptoms
were analyzed in a multivariate model, lack of health insurance and a negative PPD were
the only independent predictors of significant symptoms. Patients of Asian ethnicity tended
to lack symptoms.
Despite methodologic limitations, this study suggests that ambulatory patients with active
TB may have even milder and less specific symptoms than those described in hospitalized
patients. It also appears that patients of Asian ethnicity, a population with a high incidence
of TB in the United States, may be even less likely to report symptoms than other patients.
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. Rales may be present throughout inspiration, or may be heard only
after a short cough (post-tussive rales). 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
(amphora). Extrapulmonary signs include clubbing and findings localized to other sites of
involvement. (See "Clinical manifestations; diagnosis; and treatment of miliary
tuberculosis".)
Laboratory findings — Normal laboratory studies are the rule in most pulmonary TB. 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 abnormalities — Several studies have documented that reactivation TB
typically involves the apical-posterior segments of the upper lobes (80 to 90 percent of
patients), followed in frequency by the superior segment of the lower lobes and the anterior
segment of the upper lobes [6,11-13]. In recent large series of TB in adults, 70 to 87 percent
had the upper lobe infiltrates typical of reactivation; 19 to 40 percent also had cavities, with
visible air-fluid levels in as many as 20 percent [6,11-13].
Computed tomographic (CT) scanning is more sensitive than plain chest radiography for
diagnosis, particularly for smaller lesions located in the apex of the lung [14]. CT scan may
show a cavity or centrilobular lesions, nodules and branching linear densities, sometimes
called a "tree in bud" appearance.
The 13 to 30 percent of patients without upper lobe infiltrates are labeled as having
"atypical" radiographic patterns for adult TB [3,15,16]. These abnormalities included:
 Hilar adenopathy, sometimes associated with right middle lobe collapse
 Infiltrates or cavities in the middle or lower lung zones (see lower lung field TB
below)
 Pleural effusions
 Solitary nodules

These findings are more common in primary TB and probably represent the known
increasing incidence of primary TB in adults, rather than "atypical" forms of TB.
As many as 5 percent of patients with active TB may present with upper lobe fibrocalcific
changes thought to be indicative of healed primary TB. However, if such patients have any
pulmonary symptoms or lack serial films documenting stability of the lesion, they should
be evaluated for active TB. 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 x-rays; 23 of these patients had
pulmonary symptoms at the time of the normal radiograph [17]. In this series conducted
over a ten-year period, normal chest x-rays represented fewer than 1 percent of the
radiographs in 1988 to 1989, but increased to 10 percent from 1996 to 1997.
ENDOBRONCHIAL TUBERCULOSIS — Endobronchial TB was commonly seen with
both reactivation and primary infection in the prechemotherapy era [18-21]. In a study in a
TB sanatorium in West Virginia, 15 percent of patients had lesions in the tracheobronchial
tree at rigid bronchoscopy and 40 percent at autopsy [18]. Patients with extensive
pulmonary TB, particularly cavitary lesions, were more likely to have endobronchial
disease. It was common to find upper lung parenchymal or cavitary disease with
bronchogenic spread to the lower lung fields, presumably from pooled infected secretions.
At least two mechanisms of developing endobronchial TB are possible: direct extension to
the bronchi from an adjacent parenchymal focus, usually a cavity, or spread of organisms to
the bronchi via infected sputum from a distant site.
Endobronchial disease in children [22,23] or adults [24,25] with primary infection is more
often associated with impingement of enlarged lymph nodes on the bronchi. Inflammation
results and can be followed by endobronchial ulceration or even perforation. Complications
of endobronchial TB can include obstruction, atelectasis (with or without secondary
infections), bronchiectasis, and tracheal or bronchial stenosis [26].
Symptoms — Symptoms in clinical series include a barking cough, described in two-thirds
of patients, often accompanied by sputum production [24-28]. Patients rarely develop so-
called bronchorrhea, which is production of more than 500 mL per day of sputum [29]. In
some cases, caseous material from endobronchial lesions or calcific material from

extension of calcific nodes into the bronchi can be expectorated, which is known as
lithoptysis.
Wheezing and hemoptysis may also be seen. Lymph node rupture can be associated with
chest pain. Dyspnea, when present, may signal obstruction or atelectasis. Symptoms may
be acute in onset, and be confused with bacterial pneumonia, asthma [30], or foreign body
aspiration [31]. The clinical manifestations can also be subacute or chronic, resembling
bronchogenic carcinoma [31].
Physical findings — Diminished breath sounds, rhonchi or wheezing may be heard. The
wheeze is described as low-pitched, constant and always heard over the same area on the
chest wall.
Radiographic abnormalities — The most common radiographic finding of endobronchial
TB in adults is an upper lobe infiltrate and cavity with ipsilateral spread to the lower lobe
and possibly to the superior segment of the contralateral lower lobe. Patchy, small lower
lobe infiltrates may progress to confluence or even cavitation. Extensive endobronchial TB
can also be associated with bronchiectasis on CT scan.
When endobronchial TB occurs in patients with primary disease, 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. Because endobronchial lesions can exist without extensive
parenchymal abnormalities, 10 to 20 percent of patients may have normal chest
radiographs. However, CT scanning may reveal endobronchial lesions or stenosis.
Diagnosis — The diagnosis of endobronchial TB can be made from expectorated sputum or
bronchoscopy similar to other forms of pulmonary TB. (See "Clinical features and
diagnosis of tuberculosis in HIV-infected patients".) While it would be natural to expect
that rates of AFB smear positivity would be high with extensive endobronchial
involvement, rates of 15 to 20 percent have been reported. This lower rate may be due to
bronchial inflammatory tissue which might prevent expectoration of infected secretions
[24,25,28].
Bronchoscopy of the involved area may show erythematous, vascular and sometimes
ulcerated tissues. Granulation tissue may be bulky or polypoid. 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 [26,32]. Brushings of the lesions or lavage of the distal airways
can increase the frequency of positive smears; cultures of this material and sputum are
usually positive.
Treatment — Treatment regimens are the same for endobronchial and other forms of
pulmonary TB. (See "Treatment of tuberculosis in HIV-seronegative patients" and
"Treatment of pulmonary tuberculosis in the HIV-infected patient".) Whether concomitant
steroid therapy is helpful in the treatment of endobronchial disease is not clear. While acute
inflammatory manifestations may improve, steroids have not been clearly shown to prevent
long term complications, such as fibrosis and stenosis, in controlled studies of lymph node
TB in children [25,33,34]. Repeated dilation, stents, and resection have all been used in the
management of stenotic complications [35-37]. (See "Diagnosis and management of central
airway obstruction".)
LOWER LUNG FIELD TUBERCULOSIS — Lower lung field TB is defined as disease
located below a line traced across the hila, including the perihilar regions, on a standard PA
and lateral chest x-ray [38]. This uncommon form of the infection has varied from 2 to 9
percent in incidence in adults, depending upon the patient population studied [6,38]. As
noted above, a number of stages of TB can present with lower lobe involvement [39-41]:
 Typical reactivation TB rarely involves the superior segments of the lower lobes.
 Endobronchial TB can affect lower lung fields in both primary infection, especially
when adjacent lymph nodes are involved, and during reactivation, when spread
from upper lobe disease secondarily infects the lower lung fields.
 Typical primary tuberculosis.
 A non-specific tuberculous pneumonitis, without typical clinical features of either
primary or reactivation TB, can affect the lower lobes. Symptoms in lower lobe TB
resemble reactivation disease and are generally either subacute in onset (mean of 12
weeks) or chronic (up to six months). Compared to upper lobe TB, consolidation in
the lower lobes tends to be more extensive and homogeneous [40-42]. Cavitation
may be present, and large cavities are reported. This form of TB is frequently
initially misdiagnosed as viral or bacterial pneumonia, bronchiectasis, or carcinoma.

Elderly patients and those with diabetes, renal or hepatic disease, those receiving
corticosteroids, and those with underlying silicosis appear most at 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 tuberculous
infection in an older, tuberculin-negative population with significant underlying diseases or
anergy [39]. 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 — Rounded mass lesions can develop during primary infection or when
a focus of reactivation TB becomes encapsulated [42]. These lesions rarely cavitate. The
differential diagnosis of pulmonary coin lesions is extensive. (See "Diagnostic evaluation
and initial management of the solitary pulmonary nodule".)
Tuberculomas can be difficult to diagnose, since airway cultures are often negative. Fine
needle aspiration or open lung biopsy may be necessary for diagnosis.
COMPLICATIONS OF PULMONARY TUBERCULOSIS — Pulmonary complications of
TB include hemoptysis, pneumothorax, bronchiectasis and extensive pulmonary destruction
(including pulmonary gangrene).
Hemoptysis — Tuberculosis is thought to account for 5 to 15 percent of cases of
hemoptysis in the United States, but an increased proportion in countries with higher rates
of TB [43-45]. Hemoptysis is more common with active tuberculosis, but may also occur
after completion of effective chemotherapy. Many patients with hemoptysis are smear
positive and have cavitary disease, but the absence of these findings does not preclude
hemoptysis.
Bleeding usually is of small volume, appearing as blood-streaked sputum. Massive
hemoptysis is a rare complication of TB today. Prior to effective chemotherapy when TB
sanatoria were common, massive hemoptysis accounted for approximately 5 percent of
deaths from TB. "Rasmussen's aneurysm" causes massive hemoptysis when TB extends
into the adventitia and media of bronchial arteries, resulting in inflammation and thinning
of the vessel wall; this aneurysm subsequently ruptures into the cavity, producing
hemoptysis [46]. While this mechanism occurs, one autopsy series found Rasmussen's

aneurysms in only 6 of 80 TB patients with massive hemoptysis [47]. The pulmonary
artery, bronchial arteries without aneurysms, intercostal arteries, and other vessels
supplying the lung also have been found to be sources in cases of massive hemoptysis due
to TB.
Hemoptysis after the completion of therapy for TB only occasionally represents recurrence
of TB. Other explanations for this finding include: residual bronchiectasis, an aspergilloma
or other fungus ball invading an old healed cavity, a ruptured broncholith that erodes
through a bronchial artery, a carcinoma, or another infectious or inflammatory process.
Management — In most cases, antituberculous chemotherapy, bed rest, and sedation
control bleeding [48]. However, patients with significant TB-related hemoptysis should
undergo rapid evaluation to define the source of bleeding and facilitate immediate
intervention if this is required.
While controlled trials do not exist, several older studies indicate that after one episode of
massive hemoptysis or repeated episodes of severe hemoptysis, surgical intervention
improves survival [49-51]. Bronchial arterial embolization also has been used as a measure
to control bleeding during initial chemotherapy without surgery, to stabilize patients prior
to surgery, or in patients who are not deemed surgical candidates [52].
Pneumothorax — In the prechemotherapy era, spontaneous pneumothorax was a frequent
and dangerous complication of pulmonary TB [53]. Since the advent of chemotherapy,
spontaneous pneumothorax associated with TB has been reported in fewer than 1 percent of
hospitalized patients [54,55]. However, it still may be the most common etiology of
spontaneous pneumothorax in countries where TB is endemic.
If cases of TB in which artificial collapse was performed for therapy are eliminated,
pneumothorax appears to result from the rupture of a peripheral cavity or a subpleural
caseous focus with liquefaction into the pleural space [54,55]. Inflammation and the
creation of a bronchopleural fistula can result; such a bronchopleural fistula can seal off
spontaneously or persist. In cases of a permanent seal, the lung may reexpand
spontaneously, but more commonly tube drainage is required.
Factors preventing successful tube drainage and expansion include extensive pulmonary
parenchymal disease with large fistulas, long intervals between pneumothorax and chest

tube insertion, and the development of an empyema due to TB and bacterial superinfection.
However, successful closure of even extensive air leaks has been reported after as much as
six weeks of tube drainage accompanied by appropriate antituberculous chemotherapy [56].
Bronchiectasis — Bronchiectasis may develop after primary or reactivation TB [57-62].
After primary TB, 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 reactivation 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
reactivation TB (apical and posterior segments of the upper lobe), but may be found in
other involved areas of the lung. As noted above, bronchiectasis can also be associated with
hemoptysis.
Extensive pulmonary destruction — Rarely, TB can cause progressive, extensive
destruction of areas of one or both lungs [63,64]. This is especially in primary TB, although
occasionally lymph node obstruction of the bronchi with a combination of distal collapse,
necrosis, and bacterial superinfection can produce parenchymal destruction [64]. However,
destruction more typically results from years of chronic reactivation TB, typically in the
absence of continuous or prolonged effective chemotherapy.
Symptoms include progressive dyspnea, hemoptysis and weight loss. In one series of 18
patients with extensive destruction in one or both lungs, eight died [63]. Causes of death
were massive hemoptysis and respiratory failure, sometimes in the presence of active TB or
superinfection. Radiographically, patients had large cavities, fibrosis of remaining lung and
in some cases, air-fluid levels at the base of the destroyed lung [63,64].
The term pulmonary gangrene is used to refer to a more acute destructive process [65].
Patients with this form of TB have rapid progression from a homogeneous, extensive
infiltrate to dense consolidation. There is development of air-filled cysts which coalesce
into cavities. Necrotic lung tissue may be seen attached to the wall of the cavity.
Alternatively, pulmonary gangrene may resemble an intracavitary clot, fungus ball, or
Rasmussen's aneurysm. Pathology shows arteritis and thrombosis of the vessels supplying
the necrotic lung. While resolution with effective therapy has been reported [66], mortality

usually is high. In one small series, 75 percent of patients died [65].
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asymptomatic solitary pulmonary nodules in males. J Thorac Cardiovasc Surg 1963;
46:21.
43. Johnston, H, Reisz, G. Changing spectrum of hemoptysis. Underlying causes in 148
patients undergoing diagnostic flexible fiberoptic bronchoscopy. Arch Intern Med
1989; 149:1666.
44. McGuinness, G, Beacher, JR, Harkin, TJ, et al. Hemoptysis: Prospective high-
resolution CT/bronchoscopic correlation. Chest 1994; 105:1155.
45. Conlan, AA, Hurwitz, SS, Krige, L, et al. Massive hemoptysis. Review of 123
cases. J Thorac Cardiovasc Surg 1983; 85:120.
46. Rasmussen, V, Moore, WD (trans). Continued observations on hemoptysis.
Edinburgh Med J 1869; 15:97.
47. Thompson, JR. Mechanisms of fatal pulmonary hemorrhage in tuberculosis. Am J
Surg 1955; 89:637.
48. Corey, R, Hla, KM. Major and massive hemoptysis: reassessment of conservative
management. Am J Med Sci 1987; 294:301.
49. Bobrowitz, ID, Ramakrishna, S, Shim, YS. Comparison of medical v surgical
treatment of major hemoptysis. Arch Intern Med 1983; 143:1343.
50. Yeoh, CB, Hubaytar, RT, Ford, JM, et al. Treatment of massive hemorrhage in
pulmonary tuberculosis. J Thorac Cardiovasc Surg 1967; 54:503.
51. Amirana, M, Frater, R, Tirschwell, P, et al. An aggressive surgical approach to
significant hemoptysis in patients with pulmonary tuberculosis. Am Rev Respir Dis
1968; 97:187.

52. Uflacker, R, Kaemmerer, A, Picon, PD, et al. Bronchial artery embolization in the
management of hemoptysis: technical aspects and long-term results. Radiology
1985; 157:637.
53. Berry, FB. Tuberculous pyopneumothorax with pyogenic infection. J Thorac Surg
1932; 2:139.
54. Wilder, RJ, Beacham, EG, Ravitch, MM. Spontaneous pneumothorax complicating
cavitary tuberculosis. J Thorac Cardiovasc Surg 1962; 43:561.
55. Ihm, HJ, Hankins, JR, Miller, JE, et al. Pneumothorax associated with pulmonary
tuberculosis. J Thorac Cardiovasc Surg 1972; 64:211.
56. Auerbach, O, Lipstein, S. Bronchopleural fistulas complication pulmonary
tuberculosis. J Thorac Surg 1939; 8:384.
57. Rilance, AB, Gerstl, B. Bronchiectasis secondary to puomonary tuberculosis. Am
Rev Tuberc 1943; 48:8.
58. Roberts, JC, Blair, LG. Bronchiectasis in primary tuberculosis. Lancet 1950; 1:386.
59. Rosenzweig, DY, Stead, WW. The role of tuberculosis and other forms of
bronchopulmonary necrosis in the pathogenesis of bronchiectasis. Am Rev Respir
Dis 1966; 93:769.
60. Cohen, AG. Atelectasis of the right middle lobe resulting from perforation of
tuberculous lymph nodes into bronchi in adults. Ann Intern Med 1951; 35:820.
61. Curtis, JK. The significance of bronchiectasis associated with pulmonary
tuberculosis. Am J Med 1957; 22:894.
62. Brock, RC. Post-tuberculous broncho-stenosis and bronchiectasis of the middle
lobe. Thorax 1950;5:5.
63. Bobrowitz, ID, Rodescu, D, Marcus, H, Abeles, H. The destroyed tuberculous lung.
Scand J Respir Dis 1974; 55:82.
64. Palmer, PS. Pulmonary tuberculosis—usual and unusual radiographic presentations.
Sem Roentgenol 1979; 14:38.
65. Khan, FA, Rehman, M, Marcus, P, et al. Pulmonary gangrene occurring as a
complication of pulmonary tuberculosis. Chest 1980; 77:76.,.
66. Lorenz, R, Kraman, SS. Intracavitary mass in a patient with far-advanced

tuberculosis. Chest 1982; 82:91.

Tuberculosis transmission and control
Author
Kimon C Zachary, MD
Section Editor
C Fordham von Reyn, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Last literature review version 18.2: mayo 2010 | This topic last updated: marzo 3, 2010
(More)
INTRODUCTION — The transmission of tuberculosis (TB) in health care facilities is an
important concern. Several outbreaks of nosocomial TB in the United States accompanied
the resurgence of the disease in the general population in the late 1980s and early 1990s.
Multiple factors contributed to this problem, including deterioration of the public health
infrastructure, the human immunodeficiency virus (HIV) epidemic, and inadequate
infection control measures in health care facilities.
Enhanced infection control measures, as promoted by the Centers for Disease Control and
Prevention (CDC) guidelines, have reduced healthcare-associated transmission of TB, and
improved public health TB control programs have reduced the incidence of TB in the
community as a whole [1]. The 2004 rate was the lowest recorded in the United States since
national reporting began in 1953 [1].
The CDC has identified several key administrative control measures for a successful TB
control program [1]:
 Assigning responsibility for TB infection control
 Conducting TB risk assessment
 Developing a written TB infection control plan
 Early identification and management of patients with TB, including appropriate
institution of airborne precautions
 Environmental control measures, such as the construction and maintenance of

airborne infection isolation rooms (AII; previously called negative pressure
isolation rooms [NPIR])
 Personal protection, including the use of appropriate respirators
 Ensuring the timely availability of pertinent laboratory testing and reporting of
results
 An effective TB screening program for healthcare workers (HCWs)
 HCW training and education regarding TB symptoms, transmission, and prevention
 Using appropriate signage advising respiratory hygiene and cough etiquette
 Ensuring proper cleaning and sterilization or disinfection of potentially
contaminated equipment (usually endoscopes)
 Coordinating efforts with the local or state health department
GROUPS AT RISK — Public health measures and effective chemotherapy have
substantially reduced the incidence and prevalence of TB in the United States.
Nevertheless, certain segments of the population remain at increased risk of TB, by virtue
of having a higher prevalence of infection, a higher risk of progression to active disease if
infected, or both. (See "Epidemiology of tuberculosis".)
Groups with a higher prevalence of TB infection include [1]:
 Foreign-born persons from areas with high TB prevalence (especially those who
have arrived in the US from endemic areas less than 5 years earlier) and individuals
who travel frequently to such areas
 Homeless or marginally housed persons
 Residents and employees of congregate settings that are high-risk (eg, correctional
facilities, long-term care facilities, and homeless shelters)
 The elderly (based upon having been alive during a time of higher TB prevalence in
the United States)
 HCWs who serve patients at high risk in the United States
 HCWs, other professionals, and volunteers who travel abroad to work in healthcare
facilities or with refugees in regions in which TB is endemic
 HCWs with unprotected exposure to a patient with TB disease before the
identification and correct airborne precautions of the patient

 Certain populations who are medically underserved and who have low incomes
 Infants, children, and adolescents exposed to adults in high-risk categories
Groups with a higher risk of progression to active TB include [1]:
 Those who have been infected with TB within the previous two years
 Infants and children younger than four years of age
 Persons with a history of untreated or inadequately treated TB disease, including
those with fibrotic lesions on chest radiography suggestive of healed TB
 Persons with immunocompromising conditions, including:
 - HIV infection
 - Hematologic malignancy
 - Cancer of the head, neck and/or lung
 - Organ transplantation
 - Prolonged corticosteroid therapy
 - Treatment with other immunosuppressive agents, such as calcineurin inhibitors,
cytotoxic chemotherapeutic agents, and tumor necrosis factor alpha (TNF-alpha)
inhibitors
 Persons with other underlying medical conditions including:
 - Silicosis
 - Diabetes mellitus
 - Chronic kidney disease
 - Gastrectomy or intestinal bypass
 - Body weight 10 percent or more below ideal body weight
TRANSMISSION — Person-to-person transmission of TB occurs via inhalation of droplet
nuclei (airborne particles 1 to 5 microns in diameter). Coughing and singing facilitate
formation of droplet nuclei [2-6]. Persons with active untreated respiratory tract disease
(pulmonary or laryngeal) are contagious, particularly when cavitary disease is present or
when the sputum is AFB smear positive. However, patients with sputum smear-negative,
culture-positive pulmonary TB can transmit infection; among 844 secondary cases of TB in
the Netherlands between 1996 and 2004, 13 percent were attributable to transmission from
index patients who were smear-negative [7]. (See 'Discontinuation of TB isolation' below

and "Microbiology and pathogenesis of tuberculosis".)
NOSOCOMIAL TRANSMISSION — In the late 1980s and early 1990s, multiple urban
hospitals in the United States reported outbreaks of TB, involving both patients and HCWs
[8-12]. Several of these outbreaks involved multi-drug resistant (MDR)-TB and HIV-
infected patients, who have a high risk of developing progressive primary TB. The
propensity to develop active TB shortly after initial infection can amplify outbreaks in
hospitals or other facilities. At a 32-bed residential facility for HIV-infected persons in San
Francisco, for example, 12 cases of active pulmonary TB were diagnosed over a four month
period in late 1990 and early 1991; the isolates from the 11 patients with culture-positive
disease had similar patterns of restriction fragment length polymorphisms (RFLP) [13,14].
The New York City Department of Health, in response to growing concerns about MDR-
TB, investigated all identified cases of TB in the city over a 43 month period starting in
January, 1990 [15]. Three hundred and fifty-seven cases of TB resistant to isoniazid,
rifampin, ethambutol, and streptomycin were identified; among the 267 cases for which
RFLP analysis was available, the patterns were identical or highly similar. Eighty-six
percent of these patients were HIV-infected, and 67 percent were judged likely to have
nosocomial TB, acquired at 11 hospitals.
Procedures that can result in the dispersal of droplet nuclei have been associated with an
increased risk of TB transmission. These include endotracheal intubation, bronchoscopy,
sputum induction, aerosol treatments (eg, pentamidine), irrigation of a tuberculous abscess,
and autopsy [1].
HEALTHCARE FACILITY POLICIES — Hospital TB control programs are critical for
limiting nosocomial transmission. A study of skin test (Mantoux test) conversions in HCWs
in an urban hospital after the implementation of a TB control program in accordance with
CDC guidelines revealed an incidence of 0.38 per 100 person-years worked; 69 of 5773
susceptible employees had a skin test conversion [16]. Immediately prior to the institution
of this program, this hospital had measured an annual conversion rate of 13.2 percent
among nurses.
Development of a TB infection control plan — Every healthcare facility should have a
written TB infection control plan for each area of the facility and for each occupational

group not assigned to a specific area [1]. Periodic risk assessment is essential and should
include the following elements:
 Review of the incidence of TB and affected groups in the community, in
collaboration with the local or state department of public health
 Case surveillance, including tabulation of cases over at least the previous five years
 Review of drug susceptibility data for TB cases in the facility
 Determination of which HCWs to include in a TB screening program and
respiratory protection program, and at what frequency (see 'Contact
investigation' below)
 Prompt recognition and evaluation of suspected episodes of healthcare-associated
transmission of TB
 Periodic (preferably annual) assessment of:
 - Proper implementation of the TB infection control plan
 - Prompt identification of suspected cases and initiation of airborne precautions
 - Expert medical management of patients with suspected or confirmed TB disease
 - Pertinent maintenance of environmental controls
 Recognition and correction of lapses in infection control
Early identification of patients with active TB — Physicians must be astute in identifying
patients who may have active TB, both to benefit the patient and to minimize exposure to
HCWs and to other patients. Evaluation should start with a thorough history and physical
examination, with attention to epidemiologic risk factors, travel history, and complaints
suspicious for active TB, such as persistent (>3 weeks) cough and constitutional symptoms
(fever, drenching night sweats, unintentional weight loss).
Any hospitalized patient for whom active pulmonary or laryngeal TB is suspected should
be placed immediately in an AII room [1]. Relevant risk factors include history of
pulmonary TB, previous positive tuberculin skin test result, foreign born status with recent
immigration, homelessness, recent incarceration, weight loss and pertinent chest radiograph
findings (eg, apical infiltrate or cavitary lesion) [17].
Patients diagnosed with extrapulmonary TB require careful evaluation for pulmonary or
laryngeal TB. Immunocompromised patients with extrapulmonary TB should be presumed

to have pulmonary TB until proven otherwise with negative sputum samples, even if chest
radiography is normal.
The clinical and radiographic presentations of TB are often atypical in persons with
impaired cell mediated immunity such as HIV infection and organ transplant recipients
[18]. Such patients have an increased frequency of extrapulmonary TB and can have
pulmonary disease despite a normal chest x-ray.
The diagnosis of pulmonary TB should be pursued with sputum samples for acid-fast smear
and mycobacterial culture. If the patient is unable to produce an adequate sample, sputum
induction or bronchoscopy should be performed using appropriate precautions. (See
"Diagnosis of tuberculosis in HIV-seronegative patients".)
Sample concentration should be employed whenever possible to improve test sensitivity
[19] and rapid methods such as fluorescent microscopy should be used to optimize turn-
around time; results of acid-fast smears should be available within 24 hours [1]. Nucleic
acid amplification testing of positive sputum smears should be employed when possible.
(See "Rapid diagnostic tests for tuberculosis".)
Suspected or confirmed cases of TB should be reported promptly to the local public health
department in order to expedite contact investigation and to help plan outpatient follow-up.
Surveillance for patient-to-patient transmission of TB — Routine surveillance of active TB
cases should be monitored for clues of patient-to-patient transmission. Clues include a high
proportion of cases with prior hospitalizations in the previous year, a sudden increase in
cases (especially MDR-TB), or multiple TB patients with identical drug susceptibility
patterns (or DNA fingerprint patterns, if available).
If suspicion is aroused, HCW tuberculin skin test (TST) or interferon-gamma release assay
(IGRA) results and patient surveillance data in the suspected areas should be reviewed for
additional cases of active TB or TST/IGRA conversions. (See "Diagnosis of latent
tuberculosis infection in adults".)
Possible contacts between recently diagnosed cases and other patients with active TB
should be investigated. If the investigation supports patient-to-patient transmission, causes
for the infection control breakdown should be sought, the possibility of further exposures
(patients and HCWs) should be pursued, and the local public health department should be

notified [1].
Compliance — Multiple studies have been performed to assess compliance with infection
control programs for TB in healthcare facilities.
 One prospective study, which included direct observation in two institutions with
MDR-TB found that 19 percent of patients with pulmonary TB were not isolated on
their first hospital day, while only 8.6 percent of patients placed into TB isolation
proved to have TB [20]. Three to 4.5 percent of individuals did not wear masks to
enter the isolation rooms in both institutions, and 50 percent wore surgical masks in
one of the hospitals even after N95 respirators became available.
 In another report, direct observation in three California hospitals determined that 19
percent of patients were placed in rooms that were not designed for negative
pressure or in rooms that were not under negative pressure despite being capable of
having negative pressure (11 percent) [21].
These studies highlight the need for regular review of compliance with established infection
control policies for the control of TB.
MANAGEMENT OF SUSPECTED OR CONFIRMED ACTIVE TB
Inpatient management — Suspicion of active pulmonary TB should prompt placement in an
AII room. Such patients should be educated about the purpose of such isolation and
instructed to cover their nose and mouth when coughing or sneezing, even when in the
room. Whenever possible, procedures should be performed in the AII room to minimize
exposure to the rest of the hospital. If the patient must leave the room, a surgical mask must
be worn. All other persons entering the room must use respiratory protection, usually an
N95 mask [1].
Anti-TB treatment administered during hospitalization should be directly observed therapy
(DOT). Transitioning to outpatient management requires careful planning (see below).
TB isolation rooms — Negative pressure is employed to prevent the escape of droplet
nuclei. To accomplish this goal, doors must be kept closed and negative pressure should be
verified daily. Anterooms are desirable, but not required; when present, one should not
open both the door to the anteroom and the door to the AII room simultaneously. There
must be at least six air exchanges per hour; 12 or more exchanges per hour are preferred

and are required for any renovation or new construction. Air should be exhausted to the
exterior, far removed from any intake vents; if recirculation to general ventilation is
unavoidable, HEPA filters must be installed in the exhaust ducts [1].
Respiratory protection masks — These masks must filter particles 1 micron in diameter
with at least 95 percent efficiency (N95) given flow rates up to 50 L per minute, must fit to
a person's face with less than 10 percent seal leakage, and should be available in several
sizes to optimize fit. HCW should be fit-tested in order to determine the most appropriate
mask size with periodic repeat fit testing [1]. HCWs who are unable to use an N95 mask
due to poor fit (eg, bearded individuals and those in whom facial structure precludes a tight
seal) should use a powered air purifying respirator (PAPR). Multiple sizes of N95 masks
should be available close to AII rooms to ensure proper usage.
Controversy exists regarding the appropriate fit testing interval. The Occupational Safety
and Health Administration (OSHA) applies the general respiratory protection standard
which requires annual fit testing and medical evaluations. However, this standard was
designed to protect workers against industrial aerosols, and several medical societies have
argued that annual fit testing is not supported by available evidence and is unduly
burdensome to healthcare facilities.
Masks should be worn under the following circumstances:
 Persons entering a TB isolation room when the patient is present
 Persons present during a cough-inducing or aerosol-inducing procedure on such
patients, such as bronchoscopy, induced sputum collection, or administration of
aerosolized pentamidine
 Persons in other settings where administrative and environmental controls are
unlikely to be protective (eg, in emergency transport vehicles) [1]
These devices are designed to filter air before it is inhaled; thus, patients with known or
suspected TB should not wear these masks. Instead, when required to be outside TB
isolation rooms, such patients should wear surgical masks, which are designed to prevent
the respiratory secretions of the person wearing the mask from entering the environment
[1].
Discontinuation of TB isolation — A patient may be transferred from an AII room to

another hospital room once the diagnosis of TB has been ruled out, or when the patient is
being treated for TB and all of the following conditions are met:
 The patient is on effective therapy
 The patient is improving clinically
 Three consecutive sputum samples, obtained on different days, are smear-negative
for AFB
For patients with initially positive AFB smears, at least two weeks of TB treatment should
be administered before isolation is discontinued, although this guideline is somewhat
arbitrary and not well supported by data [2,22]. (See 'Transmission' above.)
For patients with MDR-TB, maintaining isolation throughout hospitalization is prudent [1].
Discharge planning — Cooperation between hospital staff and the local public health
department is essential. Discharge to home may be considered once the following
conditions are met:
 An outpatient appointment has been arranged with a provider who will manage TB
 Case management from the local public health department is involved and agrees
with the plan
 The patient is in possession of sufficient anti-TB medication (not just the
prescriptions) to last until the outpatient appointment
A patient may be discharged to home while still infectious, provided that the household
does not contain members at high risk for active TB (eg, immunocompromised or age less
than four) [1]. While still considered infectious, the patient should stay home as much as
possible and should wear a surgical mask when leaving the home or when receiving
visitors.
Outpatient management — Many persons with active TB will first present to an ambulatory
care site. Patients who may have active TB must be identified and evaluated promptly in
order to minimize exposure of others. Ideally, such patients should be placed in an AII
room; if unavailable, an enclosed area should be used and a surgical mask (not an N95
mask) should be placed on the patient [1]. The patient should be instructed to cover the
mouth and nose with tissues when sneezing or coughing. If an area other than an AII room
is used, it should not be used again for one hour once the patient has left.

Once a patient is diagnosed with active TB, such precautions should continue until the
patient is deemed noninfectious. Whenever possible, appointments for known TB cases
should be scheduled to avoid contact with immunocompromised patients, such as persons
with HIV.
Ambulatory care sites that treat a high volume of patients with TB or at high risk for TB
should consider having at least one AII room and should consider enhancing general
ventilation and/or using air disinfection techniques such as ultraviolet germicidal
irradiation, and/or high efficiency particulate air (HEPA) filters [1].
CONTACT INVESTIGATION — A contact investigation should be initiated to promptly
identify secondary cases of active and latent TB in the following circumstances [1]:
 Evaluation of a patient with active TB in a healthcare setting without prompt
institution of infection control measures
 Identification of active TB in a healthcare worker with exposure to others in the
healthcare setting
The investigation should proceed in collaboration with the local or state public health
department. The index case should be interviewed and his or her medical records reviewed.
An individual with AFB smear-positive involving the respiratory tract is generally
considered to have been contagious starting three months before the first smear-positive
sputum or onset of pertinent symptoms, whichever is earlier. For persons with AFB smear-
negative disease, the contagious period is considered to have begun one month before the
onset of symptoms. The contagious period is considered to end with the institution of
airborne precautions [1].
HCWs and patients with potential exposure should be screened (by symptoms and, unless
positive at baseline, TST or IGRA) as soon as possible after the exposure. If initial
screening is negative testing should be repeated 8 to 10 weeks following the end of the
exposure. Identification of individuals with LTBI or active disease should prompt
expansion of the investigation to include individuals with less intense contact with the
index patient [1].
Exposed persons with HIV infection should be evaluated for the initiation of preventive
therapy once active disease has been ruled out, regardless of TST or IGRA results [23].

Family members and other close contacts of index cases of active TB also need to be
assessed. (See "Diagnosis of latent tuberculosis infection in adults" and "Treatment of
latent tuberculosis infection in HIV-seronegative adults".)
Identification of healthcare-associated tuberculin test conversion should prompt review of
institutional TB control policy and practices [1].
INFORMATION FOR PATIENTS — Educational materials on this topic are available for
patients. (See "Patient information: Tuberculosis".) We encourage you to print or e-mail
this topic review, or to refer patients to our public web site, www.uptodate.com/patients,
which includes this and other topics.
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Centers for Disease Control and Prevention. Guidelines for preventing the
transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR
Morb Mortal Wkly Rep 2005; 54(RR17):1.
2. Sepkowitz, KA. How contagious is tuberculosis?. Clin Infect Dis 1996; 23:954.
3. Loudon, RG, Spohn, SK. Cough frequency and infectivity in patients with
pulmonary tuberculosis. Am Rev Respir Dis 1969; 99:109.
4. Loudon, RG, Roberts, RM. Droplet expulsion from the respiratory tract. Am Rev
Respir Dis 1967; 95:435.
5. Loudon, RG, Roberts, RM. Singing and the dissemination of tuberculosis. Am Rev
Respir Dis 1968; 98:297.
6. Bates, JH, Potts, WE, Lewis, M. Epidemiology of primary tuberculosis in an
industrial school. N Engl J Med 1965; 272:714.
7. Tostmann, A, Kik, SV, Kalisvaart, NA, et al. Tuberculosis transmission by patients
with smear-negative pulmonary tuberculosis in a large cohort in the Netherlands.
Clin Infect Dis 2008; 47:1135.
8. Edlin, BR, Tokars, JI, Grieco, MH, et al. An outbreak of multidrug-resistant
tuberculosis among hospitalized patients with the acquired immunodeficiency
syndrome. N Engl J Med 1992; 326:1514.
9. Beck-Sague, C, Dooley, SW, Hutton, MD, et al. Hospital outbreak of multidrug-

resistant Mycobacterium tuberculosis infections. Factors in transmission to staff and
HIV-infected patients. JAMA 1992; 268:1280.
10. Nosocomial transmission of multidrug-resistant tuberculosis to health-care workers
and HIV-infected patients in an urban hospital Florida. MMWR Morb Mortal
Wkly Rep 1990; 39:718.
11. Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected
persons Florida and New York, 1988-1991. MMWR Morb Mortal Wkly Rep 1991;
40:585.
12. Pearson, ML, Jereb, JA, Frieden, TR, et al. Nosocomial transmission of multidrug-
resistant Mycobacterium tuberculosis. A risk to patients and health care workers.
Ann Intern Med 1992; 117:191.
13. Tuberculosis outbreak among persons in a residential facility for HIV-infected
persons San Francisco. MMWR Morb Mortal Wkly Rep 1991; 40:649.
14. Daley, CL, Small, PM, Schecter, GF, et al. An outbreak of tuberculosis with
accelerated progression among persons infected with the human immunodeficiency
virus. An analysis using restriction-fragment-length polymorphisms. N Engl J Med
1992; 326:231.
15. Frieden, TR, Sherman, LF, Maw, KL, et al. A multi-institutional outbreak of highly
drug-resistant tuberculosis: epidemiology and clinical outcomes. JAMA 1996;
276:1229.
16. Larsen, NM, Biddle, CL, Sotir, MJ, et al. Risk of tuberculin skin test conversion
among health care workers: occupational versus community exposure and infection.
Clin Infect Dis 2002; 35:796.
17. Moran, GJ, Barrett, TW, Mower, WR, et al. Decision instrument for the isolation of
pneumonia patients with suspected pulmonary tuberculosis admitted through US
emergency departments. Ann Emerg Med 2009; 53:625.
18. Perlman, DC, el-Sadr, WA, Nelson, ET, et al. Variation of chest radiographic
patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-
related immunosuppression. The Terry Beirn Community Programs for Clinical
Research on AIDS (CPCRA). The AIDS Clinical Trials Group (ACTG). Clin Infect

Dis 1997; 25:242.
19. Peterson, EM, Nakasone, A, Platon-DeLeon, JM, et al. Comparison of direct and
concentrated acid-fast smears to identify specimens culture positive for
Mycobacterium spp. J Clin Microbiol 1999; 37:3564.
20. Tokars, JI, McKinley, GF, Otten, J, et al. Use and efficacy of tuberculosis infection
control practices at hospitals with previous outbreaks of multidrug-resistant
tuberculosis. Infect Control Hosp Epidemiol 2001; 22:449.
21. Sutton, PM, Nicas, M, Harrison, RJ. Tuberculosis isolation: comparison of written
procedures and actual practices in three California hospitals. Infect Control Hosp
Epidemiol 2000; 21:28.
22. Noble, RC. Infectiousness of pulmonary tuberculosis after starting chemotherapy:
review of the available data on an unresolved question. Am J Infect Control 1981;
9:6.
23. CDC. Prevention and treatment of tuberculosis among patients infected with human
immunodeficiency virus: Principles of therapy and revised recommendations.
MMWR 1998; 47(RR-20).

Treatment of tuberculosis in HIV-seronegative patients
Author
Timothy R Sterling, MD
Section Editor
C Fordham von Reyn, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Last literature review version 18.2: mayo 2010 | This topic last updated: junio 17, 2010
(More)
INTRODUCTION — The primary goals of tuberculosis treatment include [1]:
 Eradicating M. tuberculosis infection
 Preventing development of drug resistance
 Preventing relapse of infection

To achieve these objectives, combination therapy should be administered consisting of
more than one drug to which the organism is susceptible. Successful treatment of individual
cases facilitates reduction of transmission to others in the community. Directly observed
therapy (DOT) is very important for facilitating adherence and preventing the development
of drug resistance.
The American Thoracic Society (ATS), Centers for Disease Control (CDC), and Infectious
Disease Society of America (IDSA) statement on the treatment of tuberculosis is a key
summary of treatment guidelines in the United States [1]. The International Standards for
Tuberculosis Care provides important treatment recommendations for international settings
[2].
An overview of the therapy of tuberculosis, as well as features of specific antituberculous
drugs, will be provided here. Issues related to the treatment of latent M. tuberculosis
infection are discussed separately. Specific issues related to tuberculosis in HIV-infected
patients are also discussed separately. (See "Treatment of latent tuberculosis infection in
HIV-seronegative adults" and "Treatment of latent tuberculosis infection in HIV-infected
patients" and "Treatment of pulmonary tuberculosis in the HIV-infected patient" and
"Monitoring the HIV-infected patient on antituberculous medications".)
TREATMENT — Chemotherapy for tuberculosis became available with the introduction of
streptomycin (SM) and isoniazid (INH) in the 1940s and 1950s, respectively. Observation
of treatment failure with single agents (due to the emergence of drug resistance) and
subsequent development of additional agents with activity against M. tuberculosis have led
to successful treatment with combination therapy.
Several trials were conducted in the 1970s and 1980s by the British Medical Research
Council, British Thoracic Association, and Hong Kong Chest Service to evaluate the
optimal combination and duration of antituberculosis therapy [3-8]. These studies
established the efficacy of short-course (six-month) regimens with the addition of
rifampin (RIF) or pyrazinamide (PZA) to a base regimen of daily INH and SM, that
ethambutol (EMB) was roughly as effective as SM (allowing all-oral therapy), and that
PZA and EMB (or SM) was necessary only for the first two months of a six-month regimen
using INH and RIF throughout.

Initial therapy of tuberculosis should include four drugs; basic regimens for treating
patients with tuberculosis caused by organisms known or presumed to be drug-susceptible
are outlined in the Table (table 1) [1]. Each regimen has an initial phase of two months
followed by a choice of several options for the continuation phase of either four or seven
months. Drug doses are shown in the Tables (table 2 and table 3 and table 4).
The choice of treatment in the initial phase is empiric, as susceptibility data are usually not
available or are only available at the end of the initial phase of treatment. Susceptibility
data should be available at the beginning of the continuation phase and should be used to
direct therapy if drug resistance is identified.
Directly observed therapy (DOT) is the preferred strategy for treatment of all patients with
tuberculosis to assure completion of appropriate therapy and prevent emergence of drug
resistance. DOT involves providing the antituberculosis drugs directly to the patient and
watching as the patient swallows the medications. (See "Adherence to tuberculosis
treatment", section on 'Directly observed therapy'.)
Initial phase — The initial drug regimen is based on knowledge of the likely drug
susceptibility. Four drugs [isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and
ethambutol (EMB)] are used in the initial phase of previously untreated tuberculosis
because of concern for INH resistance [9]. This regimen is intended to decrease the
secondary development of resistance to RIF in populations with a high rate of primary
resistance to INH (4 percent or more). Treatment of tuberculosis with organisms resistant to
both INH and RIF (multidrug-resistant tuberculosis [MDR-TB]) is discussed separately.
(See "Diagnosis and treatment of drug-resistant tuberculosis".)
The initial phase of treatment usually consists of two months and may be administered in
one of the following schedules (table 1):
 Daily for eight weeks (Regimens 1 and 4)
 Daily for two weeks, then twice weekly for six weeks (Regimen 2). Regimen 2a is
frequently used by public health departments because the twice-weekly dosing
schedule facilitates administration of DOT.
 Three times weekly for eight weeks (Regimen 3)
If susceptibility results indicate the isolate is sensitive to INH, RIF, and PZA, then EMB

can be discontinued as it does not affect or shorten the overall treatment duration [1]. If
PZA cannot be included in the initial phase of treatment (eg, in the setting of severe liver
disease, gout, or pregnancy) the initial phase should consist of INH, RIF and EMB
administered daily for two months and the total treatment duration extended (Regimen 4).
Sputum AFB smears and cultures should be obtained at the time of completion of the initial
phase of treatment in order to identify patients at increased risk of relapse [1].
Susceptibility testing should be pursued for positive cultures. Repeat chest radiography
should be obtained for patients with negative initial cultures to evaluate for evidence of
interval improvement. It may also be useful for patients with positive initial cultures but is
not essential. (See 'Sputum monitoring' below.)
For cases in which it is not possible to establish a definitive laboratory diagnosis and
presumptive therapy is initiated (eg, based on signs and symptoms, chest radiograph,
positive tuberculin skin test, epidemiologic exposure, etc), treatment should be continued if
initial cultures are found to be positive or there is a response to treatment (eg, clinically
and/or radiographically). If culture-negative TB is suspected, a total four-month course of
antituberculosis treatment should be administered (two months of INH, RIF, PZA, EMB
followed by two months of INH and RIF for HIV-seronegative patients). If there is no
evidence of active disease, latent tuberculosis may be inferred and treatment for LTBI
should be continued accordingly. (See 'Culture negative TB' below and "Treatment of latent
tuberculosis infection in HIV-seronegative adults", section on 'Continuation of presumptive
therapy'.)
Continuation phase — The continuation phase of treatment for pulmonary tuberculosis is
administered for four or seven months and in most cases consists of INH and RIF (table 1).
Most patients are treated with a four-month continuation phase (total duration of treatment
six months) [10].
The six-month rifampin-based treatment regimen is supported by USPHS Trial 21, a
randomized trial of 1451 patients with pulmonary TB comparing the efficacy of six months
of INH and RIF (with PZA for the first two months) with nine months of INH and RIF
[11]. Patients in the six-month regimen were more likely to complete therapy (61 versus 51
percent), and relapse rates two years after completing therapy were similar in the two

groups (3.5 and 2.8 percent).
Intermittent drug administration facilitates supervision of therapy and has been shown to be
as effective as daily administration [1]. Twice weekly dosing is frequently used by public
health departments (Regimen 2a; (table 1). This practice is supported by a study of 160
patients treated with two weeks of daily directly observed therapy (INH, RIF, PZA, and
EMB) followed by twice weekly directly observed therapy for a total over 62 doses
administered over 32 weeks; the relapse rate was 1.6 percent [12].
The continuation phase should be extended to seven months (nine months total duration of
treatment) in the following circumstances [1]:
 Patients with both cavitary pulmonary TB on initial chest x-ray and positive sputum
culture after two months of initial phase treatment. The decision to prolong the
continuation phase for patients with either cavitation or positive cultures (but not
both) should be made on an individual basis.
 Patients whose initial phase of treatment did not include PZA
This practice is based on evidence from USPHS study 22, which demonstrated that among
patients on continuation phase twice weekly INH and RIF who had cavitation on initial