Tuberculosis (TB)

Back

Practice Essentials

Tuberculosis (TB) (see the image below), a multisystemic disease with myriad presentations and manifestations, is the most common cause of infectious disease–related mortality worldwide.[1, 2] After falling steadily since at least 2012, TB cases began to climb in 2020 and rose 5% in 2022 to 8,300 cases.

Although TB rates are decreasing in the United States, the disease is becoming more common in many parts of the world. In addition, the prevalence of drug-resistant TB is increasing worldwide.



View Image

Anteroposterior chest radiograph of a young patient who presented to the emergency department (ED) with cough and malaise. The radiograph shows a clas....

To help identify and manage infectious travel diseases, see Travel Medicine and Vaccination and Critical Images slideshow Travel Diseases to Consider Before and After the Trip. 

Signs and symptoms

Classic clinical features associated with active pulmonary TB are as follows (elderly individuals with TB may not display typical signs and symptoms):

Symptoms of tuberculous meningitis may include the following[1] :

Symptoms of skeletal TB may include the following:

Symptoms of genitourinary TB may include the following[1] :

Symptoms of gastrointestinal TB are referable to the infected site and may include the following[3] :

Physical examination findings associated with TB depend on the organs involved. Patients with pulmonary TB may have the following:

Signs of extrapulmonary TB differ according to the tissues involved and may include the following[4] :

The absence of any significant physical findings does not exclude active TB. Classic symptoms often are absent in high-risk patients, particularly those who are immunocompromised or elderly.

See Clinical Presentation for more details.

Diagnosis

Screening methods for TB include the following:

Obtain the following laboratory tests for patients with suspected TB:

Other diagnostic tests may warrant consideration, including the following:

Positive cultures should be followed by drug susceptibility testing; symptoms and radiographic findings do not differentiate multidrug-resistant TB (MDR-TB) from fully susceptible TB. Such testing may include the following:

Obtain a chest radiograph to evaluate for possible associated pulmonary findings. The following patterns may be seen:

Evaluation considerations for extrapulmonary TB include the following:

See Workup for more details.

Management

Physical measures (if possible or practical) include the following:

Initial empiric pharmacologic therapy consists of the following 4-drug regimens:

Special considerations for drug therapy in pregnant individuals include the following:

Special considerations for drug therapy in children include the following:

Special considerations for drug therapy in HIV-infected patients include the following:

Considerations in patients receiving antiretroviral therapy include the following:

Multidrug-resistant TB

Multidrug-resistant TB (MDR-TB) refers to isolates that are resistant to both isoniazid and rifampin (and possibly other drugs). When MDR-TB is suspected, start treatment empirically before culture results become available; obtain molecular drug susceptibility testing, if possible. Modify the initial regimen, as necessary, based on susceptibility results. Never add a single new drug to a failing regimen. Administer at least 5 drugs for the intensive phase of treatment and at least 4 drugs for the continuation phase (listed in order of preference), as follows[10, 11] :

Surgical resection is recommended for patients with MDR-TB whose prognosis with medical treatment is poor. Procedures include the following:

Latent TB

Recommended regimens for isoniazid and rifampin for latent TB have been published by the US Centers for Disease Control and Prevention (CDC)[12, 13, 14] : An alternative regimen for latent TB is isoniazid plus rifapentine as self-administered or directly observed therapy (DOT) once-weekly for 12 weeks[15, 16] ; it is not recommended for children under 2 years, individuals who are pregnant or who plan to become pregnant, or patients with TB infection presumed to result from exposure to a person with TB that is resistant to 1 of the 2 drugs.

See Treatment and Medication for more details.

Background

Tuberculosis (TB), a multisystemic disease with myriad presentations and manifestations, is the second most common cause of infectious disease–related mortality worldwide after COVID-19. The World Health Organization (WHO) has estimated that 2 billion people have latent TB and that globally, in 2021, the disease killed 1.6 million people, including 187,000 people with HIV.[17]  (See Epidemiology.)

After falling steadily since 1992, TB cases began to climb in 2020 and rose 5% in 2022 to 8,300 cases. The disease is becoming more common in many parts of the world, and the prevalence of drug-resistant TB also is increasing worldwide. Coinfection with the human immunodeficiency virus (HIV) has been an important factor in the emergence and spread of resistance.[18] (See Treatment.)

Mycobacterium tuberculosis (Mtb), a tubercle bacillus, is the causative agent of TB. It belongs to a group of closely related organisms in the M tuberculosis complex, including M africanum, M bovis, and M microti.(See Etiology.) An image of the mycobacterium is seen below.



View Image

Under a high magnification of 15549x, this scanning electron micrograph depicts some of the ultrastructural details seen in the cell wall configuratio....

The lungs are the most common site for the development of TB; a majority of patients with TB present with pulmonary complaints.[19]  Of 7174 TB cases reported in the United States in 2020, extrapulmonary TB (with no demonstrated pulmonary involvement) accounted for approximately 21% of cases. Disease in both pulmonary and extrapulmonary sites was reported in 78.9% of cases. Relative numbers are essentially unchanged since 2018, despite a 20% reduction in reported cases of TB in the United States in 2020 versus 2019.[20]  Extrapulmonary TB can occur as part of a primary or late generalized infection.(See Pathophysiology and Presentation.)

The primary screening method for TB infection (active or latent) is the Mantoux tuberculin skin test with purified protein derivative (PPD). An in vitro blood test based on interferon-gamma release assay (IGRA) with antigens specific to M tuberculosis also can screen for latent TB infection. Patients suspected of having TB should submit sputum for acid-fast bacilli (AFB) smear and culture.(See Workup.)

The usual treatment regimen for TB cases from fully susceptible M tuberculosis isolates consists of 6 months of multidrug therapy. Empiric treatment starts with a 4-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin; this therapy subsequently is adjusted according to susceptibility testing results and toxicity. Pregnant individuals, children, HIV-infected patients, and patients infected with drug-resistant strains require different regimens.(See Treatment and Medication.)

Laws vary from state to state, but infectious disease laws typically empower public health officials to investigate suspected cases of TB, including potential contacts of persons with TB. In addition, patients may be incarcerated for nonadherence to therapy. The role of public health/tuberculosis-trained nurses and digital adherence technologies increasingly is being explored and recognized, particularly in resource-limited settings.[21, 22]  

New TB treatments are being developed, and new TB vaccines are under investigation.(See Epidemiology and Treatment.)

Historical background

TB is an ancient disease. Signs of skeletal TB (Pott disease) have been found in remains from Europe from Neolithic times (8000 BCE), ancient Egypt (1000 BCE), and the pre-Columbian New World. TB was recognized as a contagious disease by the time of Hippocrates (400 BCE) when it was termed "phthisis" (Greek from phthinein, to waste away). In English, pulmonary TB was long known by the term "consumption." The discovery of a stethoscope by Laennec in 1816 and x-rays in 1895 is credited to tuberculosis.[23, 24]  Laennec's stethoscope was created to decrease the physical distance between physicians and patients to reduce the risk of transmission rather than amplifying sounds. His nephew, Mériadec Laennec, is said to have diagnosed tuberculosis in Laennec using Laennec's stethoscope. Later, on March 24, 1882, German physician Robert Koch identified and isolated M tuberculosis as the cause of tuberculosis. The observance of World Tuberculosis Day on March 24 commemorates Koch's discovery.

The worldwide incidence of TB increased with population density and urban development, so by the Industrial Revolution in Europe (1750), it was responsible for more than 25% of adult deaths. In the early 20th century, TB was the leading cause of death in the United States; during this period, however, the incidence of TB began to decline because of various factors, including the use of basic infection-control practices (eg, isolation).

Resurgence of TB

The US Centers for Disease Control and Prevention (CDC) has recorded detailed epidemiologic information on TB since 1953. Beginning in 1985, a resurgence of TB was noted with strains resistant to rifampin and isoniazid. The increase was observed primarily in ethnic minorities and especially in persons living with HIV. TB control programs were revamped and strengthened across the United States. The TB rates began to fall after 1992 due to the introduction of antiretroviral treatment (ART) and improvement in TB diagnosis, treatment, and prevention measures. An artificial decline in TB rate was noted in 2020 due to underdiagnosis and social distancing, followed by a rebound in 2021.[25]  Cases rose to 8,300 in 2022. (See Epidemiology.)

TB is most common worldwide in Africa, the West Pacific, and Eastern Europe. These regions are plagued with factors that contribute to the spread of TB, including the presence of limited resources, HIV infection, and multidrug-resistant (MDR) TB. (See Epidemiology.) The coinfection rates of TB with HIV are highest in South Africa, Nigeria, and India. Persons living with HIV are 18 times more likely to develop active tuberculosis disease compared to people without HIV, and they are 3 times more likely to die during tuberculosis treatment as per the 2020 global TB report.[26]

Drug-resistant TB

Drug resistance was first noted in the 1940s when streptomycin was formally studied as monotherapy for the treatment of TB. In 1952, the availability of isoniazid made TB curable in most patients, and the addition of rifampin in 1970 allowed therapeutic interventions to utilize multidrug regimens to decrease the risk for drug resistance.

Despite combination therapy, outbreaks of multidrug-resistant TB (MDR-TB) occurred throughout the world in the mid-1990s, including the United States, Spain, Italy, Argentina, and Russia.[27, 28, 29, 30]  Back then, the outbreak patterns mirrored the epidemiology of the HIV epidemics (especially in countries with the least infrastructure to screen and manage patients co-infected with TB and HIV), explaining why later in the late 1990s and early 2000, the number of TB cases in regions such as sub-Saharan Africa increased dramatically.[31]

Multidrug-resistant TB ( MDR-TB) is defined as resistance to isoniazid and rifampin, which are the 2 most effective first-line drugs for TB. Extensively drug-resistant TB (XDR TB) is a rare type of MDR TB that is, in addition to isoniazid and rifampin, resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie, amikacin, kanamycin, or capreomycin). XDR-TB resistant to all anti-TB drugs tested has been reported in Italy, Iran, and India and remains a risk factor for international cases due to travel and immigration.[32]  Because XDR TB is resistant to the most potent TB drugs, patients are left with treatment options that are much less effective. XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system because the persons are more likely to develop TB disease once they are infected and also have a higher risk for death once they develop TB.

WHO has kept track of TB drug resistance rates since 1994. Worldwide, 3.3% of new TB cases and 20.1% of previously treated cases are MDR. It is estimated that 490,000 cases of MDR TB existed worldwide in 2016. Certain areas, such as Belarus, Latvia, Estonia, the Russian oblasts of Ivanovo and Tomsk, and the Henan Province of China, have high rates of MDR in newly diagnosed patients (exceeding 18%).[33]  

Multiple factors contribute to the drug resistance of M tuberculosis, including incomplete and inadequate treatment or adherence to treatment, logistical issues, virulence of the organism, multidrug transporters, host genetic factors, and HIV infection. A study from South Africa found high genotypic diversity and geographic distribution of XDR-TB isolates, suggesting that acquisition of resistance, rather than transmission, accounts for between 63% and 75% of XDR-TB cases.[34]

Increased resistance rates could be explained at least partially by increased testing. In 2020, 71% (approximately 2.1 million out of 3.0 million people) with laboratory-confirmed pulmonary TB were tested for rifampicin resistance, up from 61% in 2019 and 50% in 2018. Among these 2.1 million cases, 157,903 (7.52%) had drug-resistant TB, including 25,681 cases of pre-XDR-TB or XDR-TB.[35]  

In the United States, the rate of primary resistance to an antituberculosis drug has remained stable at about 12%, with that of MDR-TB at about 1%.[33]  Of note, the COVID-19 pandemic was associated with a large proportional drop in people diagnosed with drug-resistant TB (201,997 in 2019), which mirrored the proportional drop in the number of new people diagnosed with any form of TB. This is thought to be due to the COVID-19 pandemic-related health systems disruptions and the decrease in community support systems, especially in areas endemic for TB.[36]  These disruptions translated into the lack of diagnostic services in certain areas and the lack of linkage to treatment and care worldwide.[37]

The cure rate in persons with MDR-TB is 50-60%, compared with 95-97% for persons with drug-susceptible TB.[38] The estimated cure rate for XDR-TB is 30-50%. In people who also are infected with HIV, MDR-TB and XDR-TB often produce fulminant and fatal disease; the time from TB exposure to death averages 2-7 months. In addition, these cases are highly infectious, with conversion rates of as much as 50% in exposed health-care workers.

Global surveillance and treatment of TB

As previously stated, multidrug resistance has been driven by poor adherence to TB therapies, resulting in difficulties in controlling the disease. Consequently, a global pandemic threat occurred in the late 1980s and early 1990s. Reacting to these signals, the WHO developed a plan to try to identify 70% of the world's TB cases and completely treat at least 85% by 2000.

These goals led to the creation of major TB surveillance programs and the concept of directly observed therapy (DOT), which requires a third party to witness compliance with pharmacotherapy. Thanks to these efforts, the global detection of smear-positive cases rose from 11% (1991) to 45% (2003), with 71-89% of those cases undergoing complete treatment.

Approach to TB in the emergency department

Despite the importance of early isolation of patients with active TB, a standardized triage protocol with acceptable sensitivities has yet to be developed.[39] Moran et al demonstrated that among patients with active TB in the emergency department (ED), TB often was unsuspected, and isolation measures were not used.[40]  The difficulty in establishing such a protocol only highlights the importance of the emergency physician's role in promptly identifying and isolating active TB.

A large percentage of ED patients are at increased risk of having active TB, including homeless/shelter-dwelling patients, travelers from endemic areas, immunocompromised patients, healthcare workers, and incarcerated patients. Therefore, emergency physicians must consider the management and treatment of TB as a critical public health measure in the prevention of a new epidemic.[41]

For high-risk cases, prehospital workers can help identify household contacts who also may be infected or at high risk of becoming infected.

Prehospital workers should be aware that any case of active TB in a young child indicates disease in one or more adults with close contact, usually within the same household. TB in a child is a sentinel event indicating recent transmission.

Extrapulmonary Involvement in TB

Extrapulmonary involvement occurs in one fifth of all TB cases; 60% of patients with extrapulmonary manifestations of TB have no evidence of pulmonary infection on chest radiographs or in sputum cultures.[4]

Cutaneous TB

The incidence of cutaneous TB appears low. Even in areas with high TB prevalence, such as India or China, cutaneous manifestations of TB (overt infection or the presence of tuberculids) have been found in less than 0.1% of individuals seen in dermatology clinics. Clinical manifestations may include patches and plaques (lupus vulgaris, TB verrucosa cutis), macules and papules (acute miliary TB, papulonecrotid tuberculid, lichen scrofulosorum), nodules, and abscesses (erythema induratum of Bazin, tuberculous gumma), erosions, and ulcers (tuberculous chancre, orificial TB, scrofuloderma) leading to delayed diagnosis and treatment.[42]

Ocular TB

TB can affect any structure in the eye and typically presents as a granulomatous process.[43] Ocular mycobacterial infection occurs in nonendemic areas and cannot be ruled out with negative chest imaging.[44]  Keratitis, iridocyclitis, intermediate uveitis, retinitis, scleritis, and orbital abscesses are within the spectrum of ocular disease. Choroidal tubercles and choroiditis are the most common ocular presentations of TB. Adnexal or orbital disease may be seen with preauricular lymphadenopathy. Because of the wide variability in the disease process, presenting complaints will vary.

Most often, patients will complain of blurry vision that may or may not be associated with pain and red eye. Proptosis, double vision, or extraocular muscle motility restriction may be the presenting complaint in the rare case of orbital disease. Preseptal cellulitis in children with spontaneous draining fistula also may occur. There may be ocular findings without ocular complaints in both pulmonary and extrapulmonary TB cases.

Patient Education

Patient information on TB can be found at the following sites:

Pathophysiology

Infection with M tuberculosis (Mtb) results most commonly through exposure of the lungs or mucous membranes to infected aerosols.[45] Droplets in these aerosols are 1-5 μm in diameter; in a person with active pulmonary TB, a single cough can generate 3000 infective droplets, with as few as 10 bacilli needed to initiate infection.[46]  Exposure to a similar infectious dose can occur within 5 minutes of a conversation with an infected individual. The highest number of bacilli per mL are reported of sputum with laryngeal tuberculosis, making it a highly contagious variant.[47]

Mtb are highly antigenic and initially promote a vigorous, nonspecific immune response. Their antigenicity is due to multiple cell wall constituents, including glycoproteins, phospholipids, and wax D, which activate Langerhans cells, lymphocytes, and polymorphonuclear leukocytes. After the Mtb bacilli are inhaled, they enter resident pulmonary alveolar macrophages via endocytosis and disrupt phagosome maturation through multiple pathways, including the activation of the Early Secreted Target Antigen 6 Secretion System 1 (ESX1) secretion system, delaying the T cell responses via the proteasomal pathway of antigen presentation and secretion of mycobacterial urease, superoxide dismutase, catalase, thioredoxin, and other antioxidants that neutralize reactive oxygen species generated by phagocytes.[47, 48]  The mycobacteria are released by macrophages and directly infect alveolar epithelial cells or transmigrate within infected macrophages through the lung parenchyma. The released Mtb antigens are processed by dendritic cells. The dendritic cells activate CD4+ (Th) cells through the IL-12 pathway in lymphatic tissue. The CD4+ cells then migrate to the site of infection and activate macrophages, leading to the accumulation of lytic enzymes and regulatory molecules, including tumor necrosis factor (TNF-Alpha) and transforming growth factor-beta, orchestrating granuloma formation.[49]  

Granuloma formation is the hallmark of Mtb infection. It originally was thought to have a role in "walling-off" or containing the mycobacterium, but it increasingly is recognized to play a significant role in harboring mycobacterium in a metabolically dormant state with a 10% probability of reactivation in latently infected hosts. A granuloma consists of infected and uninfected macrophages, epitheliod cells (highly stimulated macrophages), multinucleated giant cells (Langhans giant cells), dendritic cells, monocytes, eosinophils, mast cells, B and T lymphocytes, neutrophils and nonhematopoietic cells including fibroblasts, and epithelial and endothelial cells around Mtb.[50]  Molecular studies in murine models from the last 100 years have demonstrated a complex interplay that will tip the balance in favor of either the host (to contain the infection) or mycobacterium (to disseminate throughout the host). This intricate interplay is based on interactions between macrophages infected with mycobacterium, uninfected macrophages, and neutrophils at molecular levels.[51]  Granulomas can have multiple phenotypes and can be fibrotic, calcified, suppurative, cellular, or non-cellular depending upon the predominant cell type and the presence or absence of Mtb; various forms can be seen in a single host at a given time.[52, 53, 54, 55]  

The macrophages continue to be recruited and commit to granuloma formation through chemotactic pathways that depend on transcriptional induction of region of difference( RD1), ESX-1-dependent matrix metalloproteinase-9 (MMP-9), and early secretory antigenic target of T cells (ESAT-6).[50, 56, 57]  The exact mechanisms by which ESX-1 induces MMP-9 and favors macrophage recruitment remains unknown, but this hypothesis is supported by increased MMP pleural fluid levels in patients with the granulomatous pleural disease compared to non-granulomatous disease.[58]  Granuloma also serves as a vehicle for mycobacterial expansion through intracellular spread via the region of difference(RD1)/ESX1 virulence focus.

The 'mature' macrophages undergo either apoptosis or necrosis at the end of their lifecycle. During the apoptosis of mature macrophages, RD1/MMP9 signaling plays a role in chemo-attraction and recruitment of new macrophages. The new macrophages then engulf the apoptotic debris of previously infected macrophages and their mycobacterial contents. On the other hand, a foamy phenotype is induced in the macrophages by ESX-1 competent mycobacteria, leading to a switch in metabolism from glycolysis to ketosis and accumulation of lipids and fatty products within macrophages. The lipid-laden foamy macrophage contributes to the characteristic caseous necrosis and provides lipid nutrition to the mycobacterium it hosts.[59, 60, 61]  This is followed by tissue necrosis at the site (terminus Ghon focus) and involvement of nearby lymph nodes and calcification (Ghon complex). The newly infected macrophages and dendritic cells can efflux from primary granulomas to establish secondary granulomas, thus aiding dissemination.[62, 63]  The extracellular survival and dissemination of mycobacterium upon necrosis of phagocytes is supported by their cording morphology described by Koch in 1882, successfully preventing re-phagocytosis. 

MMP-1 has been implicated in the degradation of the fibrous extracellular matrix surrounding the granuloma, eventually leading to cavitation.[64]  A higher mycobacterial burden is described for cavitary lesions, which could contribute to the emergence of multi-drug resistance due to higher bacterial load and difficult drug penetration.[65, 66, 67, 68]  

When a person is infected with Mtb, the innate/acquired immune system is activated, which can suppress Mtb infection into an inactive form called latent tuberculosis infection (LTBI). In a subgroup of individuals exposed to TB, the initial innate immune response and acquired T cell response (without priming/memory) can eliminate Mtb infection.[69]  These individuals have been termed "resistors" and represent < 10% of the population.[47]  These persons will have negative tuberculin skin tests (TST) and interferon-gamma release assay (IGRA).[70]  These patients also will not benefit from LTBI treatment. Some individuals can eradicate the infection while retaining a strong memory T cell, which a positive TST or IGRA translates. This individual also will not benefit from LTBI treatment. Other individuals cannot eliminate the pathogen, so the mycobacterial infection will persist in a quiescent/latent stage that TST or IGRA can detect. However, these patients will benefit from LTBI treatment to prevent the progression to active disease.

Notably, subclinical TB is an increasingly recognized entity in which patients will intermittently have a positive mycobacterial culture (with a negative smear given the low bacilliary load) without exhibiting major clinical symptoms (they could be completely asymptomatic or have mild symptoms).[71]  Patients with subclinical TB disease can be contagious and will benefit from multi-drug therapy (as is the case for active TB). 

The lungs are the most common site for the development of TB, and the majority of patients with TB present with pulmonary complaints. However, extrapulmonary TB also can occur as part of a primary or late generalized infection. An extrapulmonary location also may serve as a reactivation site, and extrapulmonary reactivation may coexist with pulmonary reactivation.

The most common sites of extrapulmonary disease are as follows (the pathology of these lesions is similar to that of pulmonary lesions)[4] :

Infected end organs typically have high regional oxygen tension (eg, the kidneys, bones, meninges, eyes, choroids, and the apices of the lungs). M tuberculosis infection causes tissue destruction primarily by inciting intense host immune reactions to antigenic cell wall proteins.

Uveitis caused by TB is the local inflammatory manifestation of a previously acquired primary systemic tubercular infection. There is some debate about molecular mimicry and responses to noninfectious tubercular antigens, leading to active ocular inflammation without bacterial replication.

TB lesions

The typical TB lesion is an epithelioid granuloma with central caseation necrosis. The most common site of the primary lesion is within alveolar macrophages in subpleural lung regions. Bacilli proliferate locally and spread through the lymphatics to a hilar node, forming the Ghon complex.

Early tubercles are spherical, 0.5- to 3-mm nodules with 3 or 4 cellular zones demonstrating the following features:

Initial lesions may heal, and the infection may become latent before symptomatic disease occurs. Smaller tubercles may resolve completely. Fibrosis occurs when hydrolytic enzymes dissolve tubercles, and a fibrous capsule surrounds larger lesions. Such fibrocaseous nodules usually contain viable mycobacteria and are potential lifelong foci for reactivation or cavitation. Some nodules calcify or ossify and easily are seen on chest radiographs.

Tissues within areas of caseation necrosis have high levels of fatty acids, low pH, and low oxygen tension, all of which inhibit the growth of the tubercle bacillus. 

Depending on the host immune response, lesions that develop around mycobacterial foci can be proliferative or exudative. Both lesions can develop in the same host since infective dose and local immunity vary from site to site.

Proliferative lesions develop when the bacillary load is small and the host cellular immune responses dominate. In these settings, the tubercles are compact and constitute activated macrophages, proliferating lymphocytes, plasma cells, and an outer rim of fibrosis. Intracellular killing of mycobacteria is effective, and the bacillary load remains low.

Exudative lesions predominate when large numbers of bacilli are present, and host defenses are weak. Thus, loose aggregates of immature macrophages, neutrophils, fibrin, and caseation necrosis and mycobacterial growth ensue. Without treatment, these lesions progress, and infection spreads.

On another note, if the host cannot control the initial infection, the patient develops progressive primary TB with tuberculous pneumonia in the lower and middle lobes of the lung. Purulent exudates with large numbers of acid-fast bacilli can be found in sputum and tissue, and subserosal granulomas may rupture into the pleural or pericardial spaces and create serious inflammation and effusions.

Pulmonary TB lesions:

Pulmonary TB mainly is acquired through inhalation. After Mtb enters the alveoli, it translocates to the lung parenchyma through the macrophages or the transendothelial pathway. Antigen-presenting cells activate the helper T cells (TH) and stimulate differentiation into TH1 cells through a complex juxtaposition of cytokines at the molecular level. TH1 cells produce interferon-gamma (INFɣ), which in turn activates macrophages. The simultaneous innate and cellular immunity recruitment leads to granuloma formation. Lipid-laden foamy macrophage contributes to the characteristic caseous necrosis and provides lipid nutrition to the mycobacterium it hosts.[59, 60, 61]  The primary lesion can heal spontaneously with a calcified nodule (Ghon focus) left afterward. Mtb also can travel to regional lymph nodes (causing hilar and paratracheal lymphadenopathy) and other areas in the lung parenchyma, stimulating granuloma formation. The terminus Ghone focus and the calcified necrosis of the nearby lymph nodes form the Ghon complex.

The primary disease can progress in immunosuppressed individuals and children with cavitation, pleural effusions, and hematogenous spread (miliary disease). 

 

 

Etiology

TB is caused by M tuberculosis (Mtb), a slow-growing obligate aerobe and a facultative intracellular parasite. The organism grows in parallel groups called cords (as seen in the image below).



View Image

Acid-fast bacillus smear showing characteristic cording in Mycobacterium tuberculosis.

Mtb are non-spore-forming and nonmotile curved intracellular rods measuring 0.2-0.5 μm by 2-4 μm. Their cell walls contain mycolic acid-rich, long-chain glycolipids and phosphoglycolipids (mycocides) that protect mycobacteria from cell lysosomal attack[72] . The mycolic acid component also helps retain red basic fuchsin dye after acid rinsing (acid-fast stain), the basis of the acid-fast stains used for pathologic identification.

Transmission

Humans are the only known reservoir for Mtb. The organism is spread primarily via airborne aerosol from an individual in the infectious stage of TB (although transdermal and GI transmission have been reported). TB also is reported to be transmitted through organ transplant, and screening protocols are in place with close surveillance of high-risk donors. Risk factors for developing active disease after Mtb infection include recent acquisition (within 18 months), exposure to higher infectious inoculum, malnutrition, tobacco smoking, pulmonary fibrotic lesions, alcoholism, intravenous drug use, and comorbidities, including HIV, diabetes, silicosis, immunosuppression (particularly TNF-alpha inhibitors), cancer of head and neck, hematological malignancies, end-stage renal disease, chronic malabsorption, and gastrectomy [47] .

Microepidemics have occurred in closed environments such as submarines and on transcontinental flights. Populations at high risk of acquiring the infection also include healthcare workers, inner-city residents, nursing and correctional facilities home residents.

Molecular typing of M tuberculosis isolates in the United States by restriction fragment-length polymorphism analysis suggests that more than one-third of new TB cases result from person-to-person transmission. The remainder results from the reactivation of latent infection.

Verhagen et al demonstrated that large clusters of TB are associated with increased tuberculin skin test–positive contacts, even after adjusting for other transmission risk factors for transmission.[73]  The number of positive contacts was significantly lower for index cases with isoniazid-resistant TB than those with fully-susceptible TB. This suggests that some TB strains may be more transmissible than others and that isoniazid resistance is associated with lower transmissibility.

Extrapulmonary spread

Because Mtb can survive and proliferate within mononuclear phagocytes, which ingest the bacterium, Mtb can invade local lymph nodes and spread to extrapulmonary sites, such as the bone marrow, liver, spleen, kidneys, bones and joints, pleura, genitourinary tract, peritoneum, pericardium, meninges, and brain, usually via hematogenous routes.

Although mycobacteria are spread by blood throughout the body during initial infection, primary extrapulmonary disease is uncommon except in immunocompromised hosts. Extrapulmonary spread has been reported in up to 10-40% of patients with TB, with even higher rates in PLHIV.[47]  Infants, older persons, or otherwise immunosuppressed hosts cannot control mycobacterial growth and can develop disseminated (primary miliary) TB. Patients who become immunocompromised months to years after the primary infection also can develop late, generalized disease.

Role of TNF antagonists and steroids

Tumor necrosis factor–-alpha (TNF-α) is produced by infected and activated macrophages and pro-inflammatory T cells. It enhances macrophage activation, chemokine production by macrophages, and immune cell recruitment during Mtb infection. Anti-TNF-α monoclonal antibody administration may result in the dissolution of intact granulomas, the release of viable mycobacteria, and disease reactivation. This can explain the higher incidence of TB observed in patients receiving anti-TNF-α treatment. Treatment with tumor necrosis factor–alpha (TNF-α) antagonists, which are used for rheumatoid arthritis, psoriasis, and several other autoimmune disorders, has been associated with a significantly increased risk for TB.[74]  Reports have included atypical presentations, extrapulmonary and disseminated disease, and deaths. Patients scheduled to begin therapy with a TNF-α antagonist should be screened for latent TB and counseled regarding the risk for TB.

Immunosuppressive therapy includes long-term administration of systemic steroids (prednisone or its equivalent, given >15 mg/day for ≥4 wk or more) and inhaled steroids. Brassard and colleagues reported that inhaled steroids, in the absence of systemic steroids, were associated with a relative risk of 1.5 for TB. Inaheld corticosteroids at higher doses appear to increase the risk for TB.[75]

TB in children

In children younger than 5 years, the potential for the development of fatal miliary TB or meningeal TB is a significant concern. Osteoporosis, sclerosis, and bone involvement are more common in children than in adults with TB. The epiphyseal bones can be involved because of their high vascularity. Children do not commonly infect other children because they rarely develop a cough, and their sputum production is scant. However, cases of child-child and child-adult TB transmission are well documented. (See Pediatric Tuberculosis for complete information on this topic.)

Genetic factors

The genetics of tuberculosis are quite complex, involving many genes. The genetic predisposition might explain the mathematical probability of developing active disease in only a fraction of exposed individuals. Some genes involve important aspects of the immune system, whereas others involve more specific mechanisms by which the human body interacts with mycobacterium species. The following genes have polymorphisms associated with either susceptibility to or protection from tuberculosis. Additionally, regions such as 8q12 - q13 are associated with increased risk, although an exact mechanism or candidate gene has not been found.

Natural resistance-associated macrophage protein 1 (NRAMP1), CD14 and mannose-binding lectin (MBL)

Macrophages, lymphocytes, and lung parenchyma express the NRAMP1 gene. It is translated into an integral membrane protein expressed exclusively in the lysosomal compartment of monocytes and macrophages, where it can alter the intraphagosomal equilibrium to influence microbial replication. The human NRAMP1 has been renamed solute carrier family 11 (SLC11-A1).[76]

A report from Africa described an association of 4 different polymorphisms of the NRAMP1 gene with an increased risk for TB. Subjects with 2 of those 4 polymorphisms (located in an intron and a region upstream from the coding region) were at particular risk of contracting TB.[77]  The association of NRAMP1 with the risk for TB has been replicated in subsequent studies.[78, 79, 80, 81]  

MBL binds mycobacteria strongly and has a role in the uptake of mycobacterium by phagocytes. MBL insufficiency due to polymorphisms in the MBL-2 gene leads to defective opsonization and increases the incidence of recurrent infections in children and adults.[82, 83, 84]

CD14 is known to play a pivotal role in innate immunity by acting as a multifunctional receptor for bacterial cell wall components. CD14 also is involved in TLRs-mediated signaling.[85]

Polymorphisms of the NRAMP-INT4, mannose-binding lectin (MBL codons 52, 54, 57), and CD14-159 genes were explored in a study population of 250 Caucasian Polish individuals. The results suggested a possible role of CD14 and MBL molecules in the host-mycobacteria interactions. An increased serum CD14 count and MBL concentrations were noted in TB patients compared to healthy controls.[82]  

SP110

The product of this gene interacts with the interferon system and is an important aspect of the immune response. A study of 27 different polymorphisms in this gene found 3 associated with increased risk for TB; 2 of these polymorphisms were intronic, and the third was a missense mutation in exon 1134.

Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH)

The product of this gene functions to suppress cytokine signaling, an important part of inflammatory cascades. One study found that a single-nucleotide polymorphism upstream from CISH was associated with susceptibility to TB, malaria, and invasive bacterial disease. The same study found that leukocytes of persons with the risk variant for CISH had a decreased response to interleukin 235.

Immunity-related GTPase family M protein (IRGM)

The expression of this gene is induced by interferon, and the product is involved in the control of intracellular mycobacteria. In vitro analyses revealed increased expression of the IRGM gene product with the promoter variant, further underscoring the importance of this gene in the immune response to mycobacterial infection. One study found that homozygosity for a particular polymorphism in the promoter region of IRGM confers protection against TB, but only in persons of European ancestry.[86]  Another study by King et al (2011) reported that the CD-related IRGM1 polymorphism is associated with increased susceptibility to TB disease among African Americans.[87]  

Interferon-gamma (IFNG)

Interferon-gamma is a cytokine that has an important role in the immune response to intracellular infections, including viral and mycobacterial infections. It activates macrophages to kill the intracellular bacteria through reactive nitrogen and oxygen intermediates and inducing phagosome formation.[88, 89]  One polymorphism near a microsatellite in the NF kappa B binding site is associated with increased IFNG gene expression and interferon-gamma production. This polymorphism was related to protection against TB, as seen in a subsequent study.[90]

Interferon gamma receptor-1 (IFNGR1)

The product of IFNGR1 is part of a heterodimeric receptor for interferon-gamma. This has important implications for the response of this part of the immune system in the defense against certain infections.

A region of homozygosity in the region of the IFNGR1 gene has been found in a group of related children in southern Europe who were known to have a predisposition to mycobacterial infection; this predisposition, which had resulted in death in three children and chronic mycobacterial infection in a fourth, was felt to be autosomal recessive.[91] Subsequent gene sequencing showed a nonsense mutation that resulted in a nonfunctional gene product.[92]

TIR domain-containing adaptor protein (TIRAP)

Toll-like receptors (TLRs) recognize a variety of pathogens and initiate intracellular signaling through their Toll/Interleukin-1 receptor (TIR)-domains. Upon translation and activation, the adaptor protein TIRAP (TIR domain-containing adaptor protein), also known as MAL (MYD88 adapter-like), activates transcription factor NF-κB and the rest of the pro-inflammatory genes. A study of 33 polymorphisms in the TIRAP gene found that heterozygosity for a serine-to-leucine substitution was associated with protection against invasive pneumococcal disease, bacteremia, malaria, and TB.[93]

CD209

The product of the CD209 gene is involved in the function of dendritic cells, which are involved in capturing certain microorganisms. An association was found between susceptibility to TB and a polymorphism upstream from the CD209 gene in a multiracial South African population.[94]

HLA and non HLA genes

Human leukocyte antigen (HLA) and non-HLA genes also are reported in association with increased susceptibility to TB and are being studied as potential genetic markers. HLA studies from India have demonstrated an association of HLA-DR2 and HLA-DQ1 with increased susceptibility to pulmonary tuberculosis.[76]  

Epidemiology

United States

With the improvement of living conditions and the introduction of effective treatment (streptomycin) in the late 1940s, the number of patients in the United States with reported TB began to steadily decline (126,000 TB patients in 1944; 84,000 in 1953; 22,000 in 1984; 14,000 in 2004), despite explosive growth in the total population (140 million people in 1946, 185 million in 1960, 226 million in 1980).

In 2022, 8,300 TB cases were reported in the USA, compared with 7,874 cases in 2021. TB incidence increased slightly in 2022 (2.5 cases per 100,000 persons) after an artificially generated substantial decline in 2020. This drop was associated with the COVID-19 pandemic-induced social distancing, masking, and missed or delayed diagnoses. Now, after the social distancing restrictions are lifted, and people are seeking health care increasingly, reported TB cases and TB incidence in the United States are returning to pre-pandemic levels. According to the 2023 CDC report, an estimated 13 million people are living with latent TB in the USA.[95]

International

In 2023, tuberculosis (TB) was responsible for approximately 1.25 million fatalities, including 161,000 individuals co-infected with HIV. TB likely reclaimed its status as the predominant global cause of mortality from a single infectious agent, a position it held prior to being overtaken by COVID-19 for three years. It continued to be the foremost cause of death among HIV-positive individuals and played a significant role in deaths linked to antimicrobial resistance.

The same year saw an estimated 10.8 million new TB cases worldwide, comprising 6.0 million men, 3.6 million women, and 1.3 million children. TB is ubiquitous, affecting all countries and age demographics, yet it remains both preventable and curable.[1]

Demographics

In terms of demographics, the majority of reported TB cases occurred among non-US–born persons (71.4%), with the incidence rate being 15.8 times higher among non-US–born persons (12.5 cases per 100,000 persons) than US-born persons (0.8 cases per 100,000 persons). Among non-US–born persons with TB disease in 2021, the most common countries of birth included Mexico, the Philippines, India, Vietnam, and China. Among non-US–born persons, the countries of birth with the highest US incidence rates (cases per 100,000 persons from the country population living in the United States) of TB disease were the Republic of the Marshall Islands, the Republic of the Congo, Mongolia, Bhutan, Myanmar, and Somalia. In 2021, among the persons with TB disease in the United States, 36% identified as non-Hispanic Asian persons. The remainder included Hispanic or Latino persons (30.6%), non-Hispanic, African Americans (18.0%), and non-Hispanic White persons (11.2%). TB incidence rates are higher among adults than among children. Among individuals 15 years and older, the incidence rates increase with age, with adults 65 years or older having the highest TB incidence rate in 2021 (4.0 cases per 100,000 persons). In 2021, males accounted for 61.3% of TB cases in the United States, including 62.6% of cases among US-born persons and 60.7% among non-US–born persons.[96]

Prognosis

With completed therapy, a full resolution generally is expected with few complications in cases of non-MDR- and non-XDR-TB. Among published studies, the recurrence rate in patients involved in direct observed therapy(DOT) treatment ranges from 0-14%.[97] In countries with low TB rates, recurrences usually occur within 12 months of treatment completion and are due to relapse.[98] In countries with higher TB rates, most recurrences after appropriate treatment probably are due to reinfection rather than relapse.[99]

Extrapulmonary involvement, an immunocompromised state, older age, and previous infection/treatment history are considered poor prognostic markers. In a prospective study of 199 patients with TB in Malawi, 12 (6%) died. Risk factors for mortality were reduced baseline TNF-α response to stimulation (with heat-killed Mtb), low body mass index, and elevated respiratory rate at TB diagnosis.[100]

History

The following factors increase the likelihood that a patient will have tuberculosis disease (TB):

Pulmonary TB

Pulmonary tuberculosis might be asymptomatic and discovered incidentally on chest radiography. In a handful of patients, TB is accompanied by nonspecific symptoms. 

Classic clinical features associated with active pulmonary TB are as follows:

Chest pain in patients with TB can also result from tuberculous acute pericarditis. Pericardial TB can lead to cardiac tamponade or constriction.

Physical examination:

Radiography:

Laboratory findings:

Pertinent laboratory findings might include but are not limited to the following:

Diagnosis:

Miliary TB

Small (1-2 mm) granulomas develop in multiple organs, including the liver, spleen, lymph nodes, and eye.[47]  Miliary TB can manifest in multiple ways, including the following[47] :

1. Acute miliary TB

This manifests as acute or subacute illness after the initial infection seen with high-grade intermittent fevers, anorexia, weight loss, night sweats, and rigors. Two thirds of patients can have pleural (pleurisy), peritoneal (abdominal pain), and meningeal involvement (headache).

Lab findings are significant for anemia, hyponatremia, transaminitis, hypocapnia, hypoxemia, and insufficient pulmonary diffusion capacity. The smears of sputum and pulmonary secretions are not always positive. Mycobacterial blood cultures (isolators) can be positive in some cases. The best modality of diagnosis is a demonstration of caseating granulomas in histopathological tissue examination from transbronchial specimens. 

Fulminant miliary TB has been associated with severe refractory hypoxemia as well as disseminated intravascular coagulation and consequently has a poor prognosis. 

2. Cryptic miliary TB

Patients with advanced age and immunocompromised cellular immunity can have persistence of Mtb in their bloodstream with the establishment of occult foci in pulmonary, renal, genitourinary, musculoskeletal, and lymphatic systems. It can present as a fever of unknown origin. The chest x-ray and TST can be unremarkable; hence, cryptic is used. 

3. Nonreactive miliary TB

Nonreactive miliary TB represents a rare subgroup of patients in whom the characteristic granuloma formation and interactions with cellular immunity are lacking, leading to the absence of granulomas and epitheliod cells. Nonspecific areas of neutrophils and necrosing Mtb, most commonly in the liver, spleen, bone marrow, lungs, and kidney. Meningeal involvement is not seen. Nonreactive miliary TB can present as sepsis. Physical examination might reveal enlargement of the involved organ (splenomegaly or hepatomegaly). A nonspecific diffuse mottling is seen on chest radiography. Hematologic abnormalities commonly are seen, including anemia, leukemoid reaction or leukopenia, thrombocytopenia, myelofibrosis, and polycythemia. 

Extrapulmonary TB

Signs and symptoms of extrapulmonary TB may be nonspecific.[4] They can include leukocytosis, anemia, and hyponatremia due to the release of ADH (antidiuretic hormone)-like hormone from affected lung tissue.

Lymphadenitis

Generalized lymphadenopathy can be seen in 35% of extrapulmonary TB cases. The typical presentation includes painless swelling of cervical and supraclavicular lymph nodes, more so in children and PLHIV. These nodes might coalesce into a matted, non-tender mass with a fistulous tract. Diagnosis is made with fine needle aspiration or surgical excision biopsy of the lymph node.[47]

Pleural TB

Pleural involvement is seen in 20% of extrapulmonary cases and results from either a hypersensitivity reaction to Mtb antigens or Mtb spread through the parenchyma. A TB empyema may develop after rupturing the major cavity in the pleural space. This is associated with the formation of bronchopleural fistula, which historically had a higher mortality rate before the initiation of antituberculosis medications. 

Pleural involvement varies in terms of presentation depending upon the stage of TB disease. 

1. Early post-primary pleurisy with effusion

Rupture of the subpleural component of primary infection leads to the delivery of infectious and highly antigenic Mtb into the pleural space, causing inflammation and seeding involving both visceral and parietal pleura. A pleural effusion also is formed, which resolves in 2-4 months. Treatment is essential to prevent the dissemination of Mtb to other parts of the body.[104]

2. Pleurisy with effusion in chronic pulmonary TB

Pleurisy with effusion can be seen in patients with chronic pulmonary tuberculosis. The effusion may be attributed mistakenly to chronic health conditions, including cirrhosis and congestive heart failure. 

3. Pleurisy with effusion in miliary TB

Pleural effusions accompany 10-30% of miliary TB cases.[105, 106]  

The most common symptoms are as follows:

Pleural fluid is straw-colored and exudative with elevated protein levels, low to normal glucose, and a median pH of 7.3. Pleocytosis (500-2500 cells/microliter are noted) with lymphocytic predominance usually is seen, but case series also have demonstrated neutrophilic predominance 422. A low pleural concentration of adenosine deaminase excludes TB.[107, 108]

A pleural biopsy is necessary to establish a diagnosis. 

Tuberculous meningitis

Patients with subependymal tubercles are very likely to develop tuberculous meningitis. Tuberculous meningitis is caused by the rupture of a subependymal tubercule into the subarachnoid space. The rupture of the tubercle is most likely due to either head trauma or immunosuppression in the patient secondary to alcohol abuse or other immunocompromising conditions, including immunosuppressive medications. 

A gelatinous mass of tubercles usually extends from the pons or base of the brain towards optic nerves, which can get enveloped by fibrous tissue in long-standing cases. Vascular complications, including vasculitis, aneurysm formation, thrombosis, and focal hemorrhagic infarction can be seen. Intracranial tuberculomas can develop as a sequel, which essentially is a space-occupying lesion and can lead to seizures. On imaging, tuberculomas appear as multiple avascular lesions with surrounding edema.

Tuberculous meningitis occurs more frequently in young children and PLHIV.

Patients with tuberculous meningitis may present with a headache that either has been intermittent or persistent for 2-3 weeks. Fever may be low grade or absent. Subtle mental status changes may progress to coma over days to weeks. Vomiting, confusion, meningismus, and focal neurological signs also are accompanied. Severe meningitis can acutely progress to coma as well. Paresis of cranial nerves, particularly ocular nerves, might accompany be present. When perforating vessels of basal ganglia and pons are involved, lacunar infarcts or movement disorders can be observed. Hemiparesis can be seen with vasculitis of the middle cerebral artery. 

Abdominal pain, bladder or rectal incontinence, hypesthesia, anesthesia, paresthesia, or paralysis can be seen after either the development of intramedullary tuberculoma or spinal cord compression from the extradural mass. 

Lab studies:

Anemia of chronic disease commonly is seen. Hyponatremia from syndrome of inappropriate antidiuretic hormone secretion (SIADH) is common. 

CSF can have a high white cell count (from 0-1500/mm3 with lymphocytic predominance in majority and polymorphic pleocytosis earlier in the disease course), an elevated protein level, and a low glucose concentration. CSF cultures might be positive in most cases (up to 80%), and PCR (Xpert MTB/RIF) is the preferred diagnostic modality.

Imaging:

Tuberculomas (rounded lesions representing Mtb lesions) can be seen on CT/MRI of the brain. Cerebral infarction, basilar arachnoiditis, and hydrocephalus also can be seen. In concomitant spinal cord involvement cases, transverse and longitudinal myelitis, spinal tuberculomas, or abscesses can be seen on spinal imaging.[109]

The evidence of extra meningeal TB can be demonstrated in the majority of the cases.

Ventricular shunts are beneficial for cases with symptomatic hydrocephalus. Adjunctive steroids are historically reported to have a mortality benefit but do not prevent the frequency of neurological sequelae.[47]

The highest mortality has been described for the extremes of age and is directly proportional to the chronicity of the illness. Neurological disabilities are a common sequel in cases where treatment is delayed. Patients with diabetes mellitus, altered mental status, neurological deficits, hydrocephalus, vasculitis, and compromised immune system were reported to have poorer outcomes from an international prognostic score study. [110]

Skeletal TB

The most common site of skeletal TB involvement is the spine (Pott disease); symptoms include back pain or stiffness. TB can infect joints that have arthritis secondary to trauma, inflammation, or autoimmune causes. The disease can spread to adjacent spinal vertebral bodies and intervertebral discs, leading to vertebral body collapse, which is clinically manifested as kyphosis or gibbous. Lower-extremity paralysis occurs in up to half of patients with undiagnosed Pott disease.

Although any joint may be affected, tuberculous arthritis usually involves only one. The hips and knees are most commonly affected, followed by the ankle, elbow, wrist, and shoulder. Pain may precede radiographic changes in weeks to months.

Symptoms include pain and tenderness of the involved joint. Patients with advanced age are at a higher risk, and they have increased manifestations of nonspecific systemic symptoms(fever, anorexia, weight loss, chills, night sweats), multiple joint involvement, and periarticular abscess formation.[111]

Soft tissue swelling, osteopenia, periosteal thickening, and periarticular bone destruction can be seen on radiographic imaging. 

A biopsy is necessary to make a diagnosis. 

Genitourinary TB

Symptoms of genitourinary TB may include flank pain, dysuria, and frequent urination. In men, genital TB may manifest as a painful scrotal mass, prostatitis, orchitis, or epididymitis. In women, genital TB may mimic pelvic inflammatory disease. TB is the cause of approximately 10% of sterility cases in women worldwide and of approximately 1% in industrialized countries. In 90% of cases, urine analysis can show white and red blood cells with negative bacterial cultures. Mycobacterial culture of three morning urine specimens is considered diagnostic.[47]  

For complete information, go to Tuberculosis of the Genitourinary System and Imaging of Genitourinary Tuberculosis.

Gastrointestinal TB

Any site along the gastrointestinal tract may become infected with a preference for terminal ileum and caecum. Symptoms of gastrointestinal TB are referable to the infected site and include the following:

Mycobacterium can spread along the peritoneum after the rupture of lymph nodes and intraabdominal organs, leading to TB peritonitis. Granulomatous findings seen on peritoneal biopsy are used to diagnose the disease. 

Hepatic TB

Hepatic tuberculosis can be seen after seeding of the liver as part of miliary TB. It can present as fevers and abdominal pain. Liver function abnormalities and fever can mimic cholangitis. The diagnosis of primary hepatic TB is made through liver biopsy. 

TB Otitis

TB otitis is relatively rare, and diagnosis is made later in the course of the disease after the patient has failed multiple antibiotic courses intended for chronic otitis secondary to bacterial pathogens. Mtb might be acquired through aspiration through the Eustachian tube or hematogenous spread from a distant site. A direct implantation through the external auditory canal and tympanic membrane perforation also was suggested as a plausible mechanism. Clinical features are nonspecific but include painless otorrhea, tympanic membrane perforation, moderate to severe hearing loss, and facial palsy. The yield of cultures is low due to secondary infections, and diagnoses of most of the cases described in the literature have been based on pathological examination and AFB stains performed on tissue specimens. Treatment includes surgical debridement in addition to antituberculous regimens.[112, 113, 114]  

Physical Examination

Physical examination findings associated with TB depend on the organs involved. Patients with pulmonary TB have abnormal breath sounds, especially over the upper lobes or other involved areas. Rales or bronchial breath signs may be noted, indicating lung consolidation.

Signs of extrapulmonary TB differ according to the tissues involved. They may include the following:

Lymphadenopathy in TB occurs as a painless swelling of 1 or more lymph nodes. Lymphadenopathy usually is bilateral and typically involves the anterior and posterior cervical chain or supraclavicular nodes.

The absence of any significant physical findings does not exclude active TB. Classic symptoms often are absent in high-risk patients, particularly those who are immunocompromised or elderly. Up to 20% of patients with active TB may deny symptoms. Therefore, sputum sampling is essential when chest radiographic findings are consistent with TB.

Approach Considerations

The primary screening method for tuberculosis (TB) infection (active or latent) is the Mantoux tuberculin skin test with purified protein derivative (PPD). An in vitro blood test based on interferon-gamma release assay (IGRA) with antigens specific for Mycobacterium tuberculosis can also screen for latent TB infection. IGRA assays offer certain advantages over tuberculin skin testing.[115, 116]

Obtain the following laboratory tests for patients with suspected TB:

AFB stain is quick but requires a very high organism load for positivity and the expertise to read the stained sample. This test is more useful in patients with pulmonary disease. Other diagnostic testing may need to be considered, as a delay in diagnosis can increase patient mortality. Traditional mycobacterial cultures require weeks for growth and identification. Newer technologies allow identification within 24 hours.

Obtain a chest radiograph to evaluate for possible associated pulmonary findings. If chest radiography findings suggest TB and a sputum smear is positive for AFB, initiate treatment for TB. A computed tomography (CT) scan of the chest may help to define better abnormalities in patients with vague findings on chest radiography. See the images below.



View Image

Axial noncontrast enhanced computed tomography with pulmonary window shows a cavity with an irregular wall in the right apex of a 37-year-old man who ....



View Image

Coronal reconstructed computed tomography image shows the right apical cavity in a 37-year-old man who presented with cough and fever (same patient as....



View Image

Axial chest computed tomography without intravenous contrast with pulmonary window setting shows a right apical thick-walled cavity and surrounding lu....



View Image

Coronal reconstructed computed tomography image shows the consolidated, partially collapsed right upper lobe with a cavity that is directly connected ....



View Image

Axial chest computed tomography without intravenous contrast with pulmonary window setting through the mid-chest shows a large, irregular-walled cavit....



View Image

Coronal reconstructed computed tomography image shows the lingular cavity with irregular nodules and right mid-lung nodular opacities in a 43-year-old....

Technetium-99m (99m Tc) methoxy isobutyl isonitrile single-photon emission CT (SPECT) scanning for solitary pulmonary nodules yields a high predictive value for distinguishing TB from malignancy. Therefore, it has the potential to serve as a low-cost alternative when positron emission tomography (PET) scanning is not available, especially in endemic areas.[117]

Symptoms and radiographic findings do not differentiate multidrug-resistant TB (MDR-TB) from fully susceptible TB. Suspect MDR-TB if the patient has a history of previous treatment for TB, was born in or lived in a country with a high prevalence of MDR-TB, has a known exposure to an MDR-TB case, or is clinically progressing despite standard TB therapy.

Extrapulmonary TB

Extrapulmonary involvement occurs in one fifth of all TB cases, although 60% of patients with extrapulmonary manifestations of TB have no evidence of pulmonary infection on chest radiograph or sputum culture. Biopsy of bone marrow, liver, or blood cultures occasionally is necessary and may be helpful. Ocular TB can be especially difficult to identify, owing to its mimicry of other disorders and its lack of accessible sampling; a high index of suspicion is required.

The hallmark of extrapulmonary TB histopathology is the caseating granuloma, consisting of giant cells with central caseating necrosis. Rarely, if ever, are any TB bacilli seen.

Altered mental status, neck stiffness, decreased level of consciousness, increased intracranial pressure, and cranial nerve involvement can indicate tuberculous meningitis or tuberculoma. A lumbar puncture to evaluate the cerebrospinal fluid is necessary if these conditions are suspected. In addition, a tuberculoma can be substantiated by increased intracranial pressure and findings on CT or magnetic resonance image (MRI) scans.

If vertebral (Pott disease) or brain involvement is suspected, it is important to consider that a delay in treatment could have severe repercussions for the patient (ie, compression of the spinal cord and paraplegia). Consequently, further evaluation is necessary with CT scanning or MRI.

Urinalysis and urine cultures can be obtained for patients with genitourinary complaints. Although patients often are asymptomatic, significant pyuria and hematuria with no routine bacterial organisms suggest that a urine culture for acid-fast bacilli should be obtained.

Pregnancy

Pregnancy provides an opportunity to screen for TB; all pregnant individuals can undergo tuberculin skin testing. If the results are positive, chest radiography can be performed with lead shielding. Chest radiography should not be delayed during the first 3 months of pregnancy in patients with suggestive symptoms.

TB in children

The best diagnostic tests for congenital TB are the pathologic and histologic examination of the placenta and a placental culture. Mycobacterial blood cultures of the newborn also may be helpful. Treatment may be necessary until the placental culture results are negative.

Postnatal TB in infants is contracted via the airborne route. The most common findings of postnatal TB include adenopathy and a lung infiltrate. However, the chest radiographic findings may be normal in infants with disseminated disease.

Chest radiographs in children with TB may show only hilar lymphadenopathy or a patchy infiltrate. Gastric aspirates or biopsies are unnecessary if positive cultures have been obtained from the source case. Go to Pediatric Tuberculosis for complete information on this topic.

Patients with HIV infection

Individuals infected with HIV are at increased risk for TB, beginning within the first year of HIV infection.[118] All patients who are diagnosed with active TB and who are not known to be HIV positive should be considered for HIV testing.

The initiation of antiretroviral therapy (ART) decreases the risk of developing TB in these patients,[119] although the TB risk remains higher in the first 3 months of ART. The highest risk is in patients with the following factors[120] :

In a study from Durban, South Africa, nearly 20% of patients starting ART had undiagnosed, culture-positive pulmonary TB. Neither cough nor acid-fast bacillus smear were sufficiently sensitive for screening. TB sputum cultures should be attempted before ART initiation in areas with a high prevalence of TB.[121]

Patients with TB must be tested for HIV, and patients with HIV need periodic evaluation for TB with tuberculin skin testing and chest radiography. Patients with HIV and a positive tuberculin skin test result develop active TB at a rate of 3-16% per year.

Patients with TB and HIV are more likely to have disseminated disease and less likely to have upper lobe infiltrates or classic cavitary pulmonary disease. Patients with a CD4 count of less than 200/μL may have mediastinal adenopathy with infiltrates.

Sputum Smear

Patients suspected of having TB should submit sputum for AFB smear and culture. Sputum should be collected in the early morning on 3 consecutive days. In hospitalized patients, sputum may be collected every 8 hours.[122] Early-morning gastric aspirate also may produce a good specimen, especially in children.

In patients without spontaneous sputum production, sputum induction with hypertonic saline should be attempted.[123] Fiberoptic bronchoscopy with bronchoalveolar lavage (and perhaps transbronchial biopsy) can be used if other attempts at obtaining sputum specimens are unsuccessful.

Ziehl-Neelsen staining of sputum is a simple 5-step process that takes approximately 10 minutes to accomplish. While highly specific for mycobacteria, however, this stain is relatively insensitive, and detection requires at least 10,000 bacilli per mL; most clinical laboratories use a more sensitive auramine-rhodamine fluorescent stain (auramine O).

TB detection following negative smear

The absence of a positive smear result does not exclude active TB infection. Approximately 35% of culture-positive specimens are associated with a negative smear result.

Jafari et al found that an M tuberculosis–specific enzyme-linked immunospot (ELISpot) assay can differentiate TB cases with negative sputum smears from latent TB infection. In a prospective study of 347 patients suspected of having active TB who were unable to produce sputum or who had AFB-negative sputum smears, ELISpot testing of bronchoalveolar lavage fluid displayed a sensitivity and specificity of 91% and 80%, respectively, for the diagnosis of active pulmonary TB.[124]

Nucleic Acid Amplification Tests

Deoxyribonucleic acid (DNA) probes specific for mycobacterial ribosomal RNA identify species of clinically significant isolates after recovery. In tissue, polymerase chain reaction (PCR) amplification techniques can detect M tuberculosis-specific DNA sequences and, thus, small numbers of mycobacteria in clinical specimens.[125, 126]

Ribosomal RNA probes and DNA PCR assays allow identification within 24 hours. The DNA probes are approved for direct testing on smear-positive or smear-negative sputa. However, smear-positive specimens yielded higher sensitivity.

The CDC recommends performing one of these nucleic acid amplification tests when the diagnosis of pulmonary TB is being considered but has not yet been established and when the test result would alter case management or TB control activities, such as contact investigations. The CDC recommends performing the test on at least 1 respiratory specimen.[127]

A retrospective cohort analysis of 2140 patients with suspected pulmonary TB found that Mycobacterium tuberculosis direct (MTD) nucleic acid amplification testing (NAAT) yielded improved diagnostic accuracy, shortened time to diagnosis, and reduced unnecessary treatment. In all study subpopulations examined (HIV-infected, homeless, substance abuser, and foreign-born), MTD had higher positive predictive value, sensitivity, and negative predictive value than no MTD, and in all subpopulations except homeless patients, MTD had higher specificity. In HIV-infected or homeless patients, MTD substantially reduced the cost of diagnosing or excluding TB, and in substance abusers, it cut the cost of excluding TB in those with smear-negative specimens.[128, 129]  

Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA) ​is an FDA approved automated molecular test for the detection of M tuberculosis with sensitivity and specificity that approach those of culture (overall sensitivity of 89% and specificity of 99% for detection of M tuberculosis in sputum samples compared with gold standard culture testing). Sensitivity was reported 98% for smear- and culture-positive cases and 67% for smear-negative culture-positive cases. FDA approval has been extended to an indication for use of the test in removing patients from airborne isolation after one or two negative test results. The GeneXpert MTB/RIF simultaneously detects Rifampin resistance​ as well.[47]  

Other commercial NAATs include COBAS TaqMan MTB assay (Roche Molecular Diagnostics, Pleasanton, CA) and loop-mediated isothermal amplification assay (TB-LAMP; Eiken Chemical Company, Tokyo, Japan).

The caveats with PCR-based testing are that it cannot distinguish dead from viable organisms, and culture is still needed for the identification of strain and species as well as for susceptibility testing. 

CDC offers free strain typing through the National Tuberculosis Genotyping Service based on the following four typing methods[47] :

 

Culture

Culture for AFB is the most specific test for TB and allows direct identification and determination of the causative organism's susceptibility. Access to the organisms, however, may require lymph node/sputum analysis, bronchoalveolar lavage, or aspirate of cavity fluid or bone marrow. In addition, obtaining the test results is slow (3-8 wk), and they have a very low positivity in some forms of the disease.

Routine culture uses a nonselective egg medium (Lowenstein-Jensen or Middlebrook 7H10) and often requires more than 3-4 weeks because of M tuberculosis's 22-hour doubling time. Radiometric broth culture (BACTEC radiometric system) of clinical specimens significantly reduced the time (10-14 days) for mycobacterial recovery.

Newer broth culture media and systems for isolation, based on a fluorescent rather than a radioactive indicator, are available for use in clinical laboratories. The indicator is inhibited by oxygen; as mycobacteria metabolize substrates in the tubes and use the oxygen, the tube begins to fluoresce.[130]

Blood cultures

Blood cultures using mycobacteria-specific, radioisotope-labeled systems help to establish the diagnosis of active TB. However, mycobacterial bacteremia (bacilli) is detectable using blood cultures only if specialized systems are used; these bacilli have specific nutrient growth requirements not met by routine culture systems.

Such blood cultures should be used for all patients with HIV infection who are suspected of having TB because bacilli is particularly prevalent in this population. If available, these cultures should be used for any patient highly suspected of having active TB.

Drug Susceptibility Testing

Positive cultures should be followed by drug susceptibility testing. Symptoms and radiographic findings do not differentiate MDR-TB from fully susceptible TB. Suspect MDR-TB if the patient has a history of previous treatment for TB, was born in or lived in a country with a high prevalence of MDR-TB, has a known exposure to an MDR-TB case, or is clinically progressing despite standard TB therapy. Susceptibilities should be repeated if cultures remain positive after 2 months, even when initial susceptibilities have not revealed any resistance.

Drug susceptibility can be assessed via indirect testing on solid media (which takes ≥8 weeks), direct testing in liquid media (which takes ∼3 weeks), or PCR/DNA sequencing (which can provide results within hours).[47]

DNA sequencing

Because conventional drug susceptibility tests for M tuberculosis take at least 3-8 weeks, Choi et al recommend direct DNA sequencing analysis as a rapid and useful method for detecting drug-resistant TB. In their clinical study, the turnaround time of the direct DNA sequencing analysis was 3.8 +/- 1.8 days. The sensitivity and specificity of the assay were 63.6% and 94.6% for isoniazid, 96.2% and 93.9% for rifampin, 69.2% and 97.5% for ethambutol, and 100% and 92.6% for pyrazinamide, respectively.[131]

Newer assays detect mutations in the 81-base-pair rpoB gene, which encodes the β-subunit of RNA polymerase and correlates with greater than 96% of RIF resistance. ​The GeneXpert MTB/RIF assay detects mutations in the rpoB gene and has a sensitivity of 95% and specificity of 98% compared to culture.​ 

Xpert MTB/RIF Ultra is more sensitive than Xpert MTB/RIF but with slightly less specificity. 

Multiple line probe assays are commercially available,[47]  including:

Automated molecular testing

An automated molecular test that uses sputum samples for detecting M tuberculosis and resistance to rifampin has been developed. In studies conducted in low-income countries, the sensitivity for TB was 98.3% using a single smear-positive sputum sample. Sensitivity with a single smear-negative sputum sample was 76.9%, but it increased to 90.2% when 3 samples were tested. The test correctly identified 94.4% of rifampin-resistant organisms and 98.3% of rifampin-sensitive organisms.[132, 133]

MODS and TLA assays

Microscopic-observation drug susceptibility (MODS) and thin-layer agar (TLA) assays are inexpensive, rapid alternatives to conventional and molecular TB drug susceptibility testing methods. The WHO has endorsed the MODS assay as a direct or an indirect test for rapid screening of patients with suspected MDR-TB. The evidence is insufficient to recommend using the TLA assay for rapid screening, but this assay is a promising diagnostic technique.[134]

The Hardy TB MODS Kit (Hardy Diagnostics, Santa Maria, CA​) produces results comparable to those of the conventional MODS. It can also detect INH and RIF resistance in a Biosafety Level 2 setting.

Additional rapid tests

Other rapid tests also are available, such as BACTEC-460 (Becton-Dickinson), ligase chain reaction, and luciferase reporter assays (within 48 h) (Franklin Lakes). These tests have been developed for rapid drug-susceptibility testing, and results can be available within 10 days. Drug-resistance tests such as the FASTPlaque TB-RIF for rifampin resistance can be used after growth in semiautomated liquid cultures such as BACTEC-460; rifampin resistance can be used as a surrogate marker for isoniazid resistance.

Chest Radiography

Obtain a chest radiograph to evaluate for possible TB-associated pulmonary findings (demonstrated in the images below). A traditional lateral and posteroanterior (PA) view should be ordered. In addition, an apical lordotic view may permit better visualization of the apices and increase the sensitivity of chest radiography for indolent or dormant disease.



View Image

This radiograph shows a patient with typical radiographic findings of tuberculosis.



View Image

Anteroposterior chest radiograph of a young patient who presented to the emergency department (ED) with cough and malaise. The radiograph shows a clas....



View Image

Lateral chest radiograph of a patient with posterior segment right upper lobe density consistent with active tuberculosis. Image courtesy of Remote Me....



View Image

This chest radiograph shows asymmetry in the first costochondral junctions of a 37-year-old man who presented with cough and fever. Further clarificat....



View Image

This posteroanterior chest radiograph shows right upper lobe consolidation with minimal volume loss (elevated horizontal fissure) and a cavity in a 43....



View Image

The posteroanterior chest radiograph shows a large cavity with surrounding consolidation in the lingular portion of the left upper lobe in a 43-year-o....

The chest film also is useful to screen for sarcoidosis, which closely imitates the clinical course of ocular TB. Radiologists look more decisively for signs of TB or sarcoid if the requesting physician specifies an interest in these.

Chest radiographs may show a patchy or nodular infiltrate. Although TB can affect any part of the lung, the upper lobes most commonly are involved. The lordotic view may better demonstrate apical abnormalities.

The following patterns may be seen on chest radiographs:

Chest radiography consistent with TB indicates active disease in the symptomatic patient, even without a diagnostic sputum smear. Similarly, normal chest radiographic findings in the symptomatic patient do not exclude TB, particularly in an immunosuppressed patient.

Primary TB

In primary active TB, radiographic features of pulmonary tuberculosis are nonspecific, sometimes even normal. The chest radiograph typically shows a pneumonia-like picture of an infiltrative process in the middle or lower lung regions, often associated with hilar adenopathy and atelectasis.

Primary tuberculosis (TB) is more likely to mimic the appearance of routine community-acquired pneumonia (CAP) on chest radiography than reactivation TB. Studies have shown that primary TB and CAP may be associated with pleural effusion and cavitation.

Reactivation TB

In classic reactivation TB, pulmonary lesions are located in the posterior segment of the right upper lobe, the apicoposterior segment of the left upper lobe, and the apical segments of the lower lobes. Cavitation is most common; healing of tubercular regions results in the development of a scar, with loss of lung parenchymal volume and calcification.

TB and HIV infection

In patients with HIV infection or another immunosuppressive disease, lesions often are atypical. Up to 20% of HIV-positive patients with active TB have normal chest radiographic findings. 

Pulmonary TB is the typical upper-lobe cavitary disease when cell-mediated immunity is partially compromised. 

In late HIV infection, a primary TB-like pattern may be evident, with diffuse interstitial or miliary infiltrates, little or no cavitation, with intrathoracic lymphadenopathy. 

Healed and latent TB

Old, healed TB presents a different radiographic appearance, with dense pulmonary nodules in the hilar or upper lobes, with or without calcifications. Smaller nodules can be seen in the upper lobes with or without fibrotic scars. Nodules and fibrotic lesions are well-demarcated, have sharp margins, and are dense.

Patients with nodular or fibrotic scars on chest radiography and positive PPD results should be treated as latent carriers. Calcified nodular lesions (granulomas) or apical pleural thickening indicate a lower risk of conversion.

Miliary TB

In disseminated/miliary TB, the chest radiograph commonly shows a miliary pattern, with 2-mm nodules that, histologically, are granulomas disseminated like millet seeds throughout the lung. However, chest radiographic patterns can vary, including upper lobe infiltrates with or without cavitation.

Pleural TB

In pleural tuberculosis, the pleural space can be involved in 2 ways: (1) a hypersensitivity response can cause pleuritic pain and fever, or (2) an empyema can be present that can be seen on chest radiographs, with associated pleural effusions.

See the following articles for more information on TB imaging studies:

Screening

Tuberculin skin test

The primary screening method for TB infection (active or latent) is the Mantoux tuberculin skin test with PPD. Tuberculin sensitivity develops 2-10 weeks after infection and usually is lifelong. Tuberculin skin testing is based on the fact that TB infection induces a strong, cell-mediated immune response that results in a measurable delayed-type hypersensitivity response to intradermal injection of tuberculin PPD.

The PPD test involves an intradermal injection of 5 units of PPD (0.1 mL), preferably with a 26, 27, or 30-gauge needle. The results should be read between 48 and 72 hours after administration. Induration of less than 5 mm in immunologically intact individuals constitutes a negative result.

Population-based criteria for PPD positivity are as follows:

Reactions in patients who have received the bacillus Calmette-Guérin (BCG) vaccine should be interpreted in the same way as the reactions above, regardless of BCG history, according to guidelines from the CDC.[135]

The 'booster effect' (a positive tuberculin test result after a negative one) develops within several days after a first injection and may be persistent. The booster effect causes interpretative issues as the negative test result followed by a positive test result approximately 10 weeks later could be secondary to a repeat infection. This issue is resolved by retesting the patients 1 to 3 weeks after the first test. If the second test result is positive, this indicates boosting rather than recent tuberculin conversion.[47]

The caveats to be considered while interpreting TST results include the following:

1. The 'booster effect' (a positive tuberculin test result after a negative one) develops within several days after a first injection and may be persistent. The booster effect causes interpretative issues as the negative test result followed by a positive test result approximately 10 weeks later could be secondary to a repeat infection. This issue is resolved by retesting the patients 1 to 3 weeks after the first test. If the second test result is positive, this indicates boosting rather than recent tuberculin conversion.[47]

2. Protein malnutrition, sarcoidosis, concurrent viral infections, vaccination with live-virus vaccines (measles, smallpox), reticuloendothelial disease, and immunosuppressive therapy may cause false-negative tuberculin reactions. 

3. TST results are negative during the initial infection's first 3 to 9 weeks. 

4. Delayed reactivity has been reported among Indochinese immigrants with induration of less than 10 mm at 48 to 72 hours, which subsequently increases to greater than 10 mm when the skin test is read again at 6 days.[47]

5. The American Thoracic Society (ATS), the Infectious Diseases Society of America (IDSA), and the CDC recommend an interferon-γ release assay rather than the TST for people from countries that vaccinate with BCG. 

Interferon-gamma release assay

An in vitro blood test based on IGRA with antigens specific for M tuberculosis can also be used to screen for latent TB infection and offers certain advantages over tuberculin skin testing.[115, 116] The 2 currently available tests are (1) QuantiFERON-TB Gold In-Tube (QFT-GIT), an enzyme-linked immunosorbent assay (ELISA) based on ESAT-6, CFP-10, and TB 7.7 antigens, and (2) T-SPOT.TB, an enzyme-linked immunosorbent spot (ELISpot) assay based on ESAT-6 and CFP-10 antigens.

IGRA tests measure T-cell interferon-gamma response to antigens highly specific for M tuberculosis and absent from the BCG vaccine and M avium.[136] Overall, the sensitivity and specificity of IGRA are comparable to those of tuberculin skin testing; however, unlike tuberculin skin testing, these tests do not require a second visit for a reading. Results are reported as positive, negative, or indeterminate. Patients with an indeterminate result may have evidence of immunosuppression and may be nonreactive on skin testing.[137]

Advantages of IGRA compared with PPD include the following:

Disadvantages of IGRA include the following:

Screening test accuracy

Neither tuberculin skin testing nor IGRA testing is sufficiently sensitive to rule out TB infection.[138] Approximately 20% of patients with active TB, particularly those with advanced disease, have normal PPD test results. In addition, caution is recommended in interpreting these tests in infants and patients with immunosuppressive conditions. [136]

A systematic review of QuantiFERON-TB Gold (QFT-G)/Gold in-Tube (QFT-GIT) and T-SPOT.TB by Chang and Leung concluded that QFT-G had the highest positive likelihood ratio (48.1) for latent TB infection and that T-SPOT.TB had the best negative likelihood ratio (0.10). A negative T-SPOT.TB results in middle-aged and older patients, making active TB very unlikely.[139]

Results from a study by Leung et al indicated that tuberculin skin testing is not predictive of the subsequent development of active TB.[140] The authors followed 308 men with increased risk for TB because of silicosis. A positive T-SPOT.TB finding was associated with a relative risk of 4.5 for subsequent TB in the group overall and a relative risk of 8.5 among the men who did not receive preventive treatment for latent TB. The CFP-10 spot count was more predictive than the ESAT-6 spot count.

In a study by Diel et al, all subjects who developed active TB within 4 years after exposure to a smear-positive index case had positive results using QFT-GIT. These researchers concluded that QFT-GIT was more reliable than tuberculin skin testing for identifying patients, especially children, who will soon progress to active TB.[141]

In a study of kidney-transplant recipients, positive ELISpot assays predicted the subsequent development of TB in patients who did not have a significant tuberculin skin test reaction or risk factors for TB infection. Active TB developed after kidney transplantation in 4 of 71 patients (6%) with positive ELISpot assays but in none of the 201 patients with negative or indeterminate ELISpot results.[142]

Other Tests

Urine antigen testing

Lateral flow urine lipoarabinomannan (LF-LAM) assay (Abbott, Abbott Park, IL)​ is being used in diagnosing TB in patients with advanced AIDS, particularly in countries where coinfection is highly prevalent.​ The sensitivity for TB in HIV-uninfected persons is less than 25%.​[47]

Stool Testing

Xpert MTB/RIF assay is employed for TB diagnosis in the pediatric population based on updated WHO recommendations. The utility in the adult population is uncertain, and studies are under process.[143, 144, 145]  

Approach Considerations

Isolate patients with possible tuberculosis (TB) infection in a private room with negative pressure (air exhausted to outside or through a high-efficiency particulate air filter). Medical staff must wear high-efficiency disposable masks sufficient to filter the tubercle bacillus. Continue isolation until sputum smears are negative for 3 consecutive determinations (usually after approximately 2-4 wk of treatment). Unfortunately, these measures are neither possible nor practical in countries where TB is a public health problem.

Drug therapy

For initial empiric treatment of TB, start patients on a 4-drug regimen: isoniazid, rifampin, pyrazinamide, and ethambutol. Once the TB isolate is known to be fully susceptible, ethambutol can be discontinued.[5]

Patients with TB receiving pyrazinamide should undergo baseline and periodic serum uric acid assessments, and patients with TB who are receiving long-term ethambutol therapy should undergo baseline and periodic visual acuity and red-green color perception testing. The latter can be performed with a standard test, such as the Ishihara test for color blindness.

After 2 months of therapy (for a fully susceptible isolate), pyrazinamide can be stopped. Isoniazid plus rifampin are continued as daily or intermittent therapy for 4 more months. If isolated isoniazid resistance is documented, discontinue isoniazid and continue treatment with rifampin, pyrazinamide, and ethambutol for 6 months. Therapy must be extended if the patient has cavitary disease and remains culture-positive after 2 months of treatment.

Directly observed therapy (DOT) is recommended for all patients. With DOT, patients on the above regimens can be switched to 2- to 3-times per week dosing after an initial 2 weeks of daily dosing. Patients on twice-weekly dosing must not miss any doses. Prescribe daily therapy for patients on self-administered medication.

Monitoring

Patients diagnosed with active TB should undergo sputum analysis for Mycobacterium tuberculosis weekly until sputum conversion is documented. Monitoring for toxicity includes baseline and periodic liver enzymes, complete blood cell (CBC) count, and serum creatinine.

Seizures from isoniazid overdose

A special regimen exists for patients with TB who are actively seizing or who have overdosed on antimycobacterial medication. In these patients, an overdose of isoniazid should be suspected. The administration of diazepam can be attempted to control seizure activity, but IV pyridoxine is the drug of choice in a gram-for-isoniazid-ingested-gram dose. If the ingested dose is unknown, 5 g of pyridoxine can be used empirically. For awake and alert patients, an oral dose of activated charcoal (1 g/kg) with sorbitol can be administered.

Shorter duration regimens

Newer 4-month regimens are being adapted as the data from new clinical trials becomes available. TBTC Study 31/A5349 involved 2516 participants from 34 clinical sites in 13 countries. All patients were AFB smear positive, and 1701 had cavitary lung disease. A 4-month regimen consisting of isoniazid, rifapentine, moxifloxacin, and pyrazinamide was noted to be non-inferior to a standard 6-month regimen of isoniazid, rifampin, pyrazinamide, and ethambutol.[146]  

 

Treatment During Pregnancy

Pregnant patients with active TB should be treated, even in the first stage of pregnancy. Isoniazid, rifampin, and ethambutol may be used. In the United States, pyrazinamide is reserved for women with suspected multidrug-resistant TB (MDR-TB). Elsewhere in the world, pyrazinamide is commonly used in pregnant individuals with TB. Streptomycin should not be used because it has been shown to have harmful effects on the fetus.

Preventive treatment is recommended during pregnancy, especially in the following types of patients:

Pregnant individuals are at an increased risk for isoniazid-induced hepatotoxicity and should undergo monthly alanine aminotransferase (ALT) monitoring while on treatment. This risk continues 2-3 months into the postpartum period. Pyridoxine should also be administered to pregnant patients receiving isoniazid.

Breastfeeding can be continued during preventive therapy. Many experts recommend supplemental pyridoxine for the breastfed infant.

Lin et al reported that individuals diagnosed with TB during pregnancy are at an increased risk of having children who are of low birth weight and are small for their gestational age. However, preterm birth was not more common in pregnant individuals with TB.[147]

Treatment in Children

Most children with TB can be treated with isoniazid and rifampin for 6 months, along with pyrazinamide for the first 2 months if the culture from the source case is fully susceptible.

For postnatal TB, many experts increase the treatment duration to 9 or 12 months because of the possible impaired immune system in children younger than 12 months. The Bacillus Calmette-Guérin (BCG) vaccine is not recommended in infants in the United States but is commonly used worldwide.

Isoniazid tablets may be crushed and added to food. Isoniazid liquid without sorbitol should be used to avoid osmotic diarrhea, which can cause decreased absorption.

Rifampin capsules may be opened, and the powder added to food. If rifampin is not tolerated, it may be taken in divided doses 20 minutes after light meals.

Ethambutol often is avoided in young children because of difficulties monitoring visual acuity and color perception. However, studies show that ethambutol (15 mg/kg) is well tolerated and can prevent further resistance if the child is infected with a resistant strain. Go to Pediatric Tuberculosis for complete information on treating children.

Bedaquiline is also a consideration as part of a 4-drug regimen for multidrug-resistant pulmonary tuberculosis in children aged 5 years or older when an effective treatment regimen cannot otherwise be provided.

Treatment in HIV-Infected Patients

Treatment regimens for active or latent TB in patients with HIV infection are similar to those used in HIV-negative patients, but dose adjustments may be necessary.[6, 7] The most significant differences involve the avoidance of rifampin in patients who are on protease inhibitors. Rifabutin may be used in place of rifampin in such patients.

Antiretroviral therapy

Patients with HIV and TB may develop a paradoxical response (immune reconstitution inflammatory syndrome [IRIS]) when starting antiretroviral therapy. This response has been attributed to a stronger immune response to Mtb. Clinical findings include fever, worsening pulmonary infiltrates, and lymphadenopathy.

However, in an open-label, randomized trial, Abdool Karim et al concluded that initiating antiretroviral therapy during TB therapy significantly improved patient survival. In this study, the mortality rate with simultaneous initiation of antiretroviral therapy and TB therapy was 5.4 deaths per 100 person-years (25 deaths in 429 patients), compared with 12.1 deaths per 100 person-years (27 deaths in 213 patients) with antiretroviral therapy started after the completion of TB therapy, a relative reduction of 56%.[8]

Subsequent studies by these and other researchers found that starting antiretroviral therapy early (eg, within 4 weeks after the start of TB treatment) reduced progression to AIDS and death. In patients with higher CD4+ T-cell counts, however, deferring initiation of antiretroviral therapy until the continuation phase of TB treatment may be a reasonable strategy because the risks for IRIS and for adverse events that necessitate switching of antiretroviral drugs are lower with later initiation of antiretroviral therapy.[9]

Treatment length and recurrence rate

Swaminathan et al reported a significantly lower bacteriologic recurrence rate with 9 months, instead of 6 months, of an intermittent (3 times/wk) 4-drug regimen in patients with HIV infection and newly diagnosed TB. Mortality was similar in both groups. The rate of acquired rifampin resistance was high in both groups and was not altered by the longer TB treatment.[6]

Tuberculous meningitis and the role of steroids

In patients with tuberculous meningitis, dexamethasone historically is added to routine 4-drug therapy to reduce complications. However, in a most recent randomized control trial by Donovan et al (2023), adjunctive dexamethasone, as compared with placebo, did not confer a benefit concerning survival or any secondary endpoint.[148]  

Treatment of Tuberculosis Resistant to a Single Drug

The CDC reported that 9.4% of TB cases were resistant to isoniazid in 2018 (16% were MDR-TB).[149] TB resistant to isoniazid can be treated with rifampin, pyrazinamide, and ethambutol for 6 months. Therapy should be extended to 9 months if the patient remains culture-positive after 2 months of treatment.

TB that is resistant to only rifampin (an unusual occurrence) can be treated with isoniazid, a fluoroquinolone (levofloxacin or moxifloxacin), and ethambutol for 12-18 months, depending on clinical response. Therapy should include pyrazinamide for at least the first 2 months of treatment.

A CDC analysis of resistance to pyrazinamide in US cases showed that such resistance increased from 2% in 1999 to 3.3% in 2009. Pyrazinamide monoresistance was associated with younger age, Hispanic ethnicity, HIV infection, and extrapulmonary disease.[150, 151] TB resistant to pyrazinamide can be treated with isoniazid and rifampin for 9 months. Ethambutol should be included for the first 2 months of treatment.

Treatment of Multidrug-Resistant Tuberculosis

Multidrug-resistant TB (MDR-TB) refers to isolates that are resistant to both isoniazid and rifampin (and possibly other drugs). When MDR-TB is suspected because of a relevant history or epidemiologic information, start treatment empirically before culture results become available; obtain molecular drug susceptibility testing, if possible. Once results are known, the regimen is modified according to susceptibilities. (Costs are many times higher for the treatment of MDR-TB.) Never add a single new drug to a failing regimen.

Administer at least 5 drugs for the intensive phase of treatment and at least 4 drugs for the continuation phase (listed in order of preference), as follows[10, 11] :

Successful MDR-TB treatment is more likely associated with factors such as lower prior patient exposure to anti-TB drugs, a higher number of anti-TB drugs to which the infection is still susceptible, and a shorter time since the first TB diagnosis (indicating less advanced disease).

The intensive-phase treatment for MDR-TB should be 5-7 months, followed by the continuation phase, so that the total duration of treatment is 15-24 months after culture conversion. The drugs should be prescribed daily (no intermittent therapy), and the patient should always be on DOT. Weekend DOT may not be possible; therefore, giving self-administered oral drugs on Saturdays and Sundays may be reasonable. All patients should be closely observed for 2 years after completion of treatment, with a low threshold for referral to TB centers.

The diarylquinoline antimycobacterial, bedaquiline (Sirturo), was approved by the FDA in December 2012 as part of a 22-week multidrug regimen for pulmonary MDR-TB. Approval was based on phase 2 data that showed bedaquiline significantly improved time to sputum culture conversion and included 2 consecutive negative sputum cultures collected at least 25 days apart during treatment. At week 24, sputum culture conversion was observed in 77.6% of patients in the bedaquiline treatment group compared with 57.6% of patients in the placebo treatment group (p=0.014).[152, 153]

In another phase II study by Diacon et al, bedaquiline (TMC207) added to standard therapy for MDR-TB reduced the time to conversion to a negative sputum culture compared with placebo and increased the proportion of patients with the conversion of sputum culture (48% vs. 9%). [154]

Bedaquiline gained FDA approval in August 2019 for adolescents aged 12 years or older and for children as young as 5 in May 2020. This approval was based on evidence from a single-arm, open-label, phase 2 study that enrolled 15 pediatric patients with confirmed or probable MDR-TB infection. The patients were treated with the recommended dosage of bedaquiline for 24 weeks in combination with a background regimen.[155]

Provisional guidelines from the CDC include the use of bedaquiline on a case-by-case basis in children, HIV-infected persons, pregnant individuals, persons with extrapulmonary MDR-TB, and patients with comorbid conditions on concomitant medications when an effective treatment regimen cannot otherwise be provided.[156, 157]

The diagnosis of extensively drug-resistant TB (XDR-TB) is established with an isolate that is resistant to isoniazid, rifampin, at least 1 of the quinolones, and at least 1 injectable drug. Treatment options for XDR-TB are very limited, and XDR-TB carries a very high mortality rate.

In August 2019, the FDA approved pretomanid, a nitroimidazooxazine, for adults with XDR-TB, treatment-intolerant TB, or nonresponsive MDR-TB. Pretomanid kills actively replicating M tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production. Efficacy was primarily demonstrated in a study of 109 patients treated with pretomanid plus bedaquiline and linezolid. Of the 107 patients evaluated 6 months after the end of therapy, treatment was successful in 95 (89%), far exceeding the success rates of previously available treatments.[158, 159]

A CDC analysis of the prevalence, trends, and risk factors for pyrazinamide polyresistance was associated with Hispanic ethnicity, Asian race, previous TB diagnosis, and normal chest x-ray and inversely associated with age 45 years and older. Pyrazinamide resistance in multidrug-resistant cases was associated with female sex and previous TB diagnosis. Bacterial lineage, rather than host characteristics, was the primary predictor of pyrazinamide resistance in M tuberculosis cases.[150, 151]

Surgical resection

Surgical resection of an infected lung may be considered to reduce the bacillary burden in patients with MDR-TB. Surgery is recommended for patients with MDR-TB whose prognosis with medical treatment is poor. Surgery can be performed with a low mortality rate (< 3%), with prolonged periods of a chemotherapeutic regimen used for more than 1 year after surgery.

Procedures include segmentectomy (rarely used), lobectomy, and pneumonectomy. Pleurectomies for thick pleural peel are rarely indicated.

Intraoperative infection of uninvolved lung tissue has been observed in resections. Complications include the usual perioperative complications, recurrent disease, and bronchopleural fistulas.

Treatment of Latent TB

The antimycobacterial rifapentine (Priftin), which was previously approved for use against active pulmonary TB caused by Mycobacterium tuberculosis, has been approved by the US Food and Drug Administration (FDA) for use, in combination with isoniazid, in the treatment of latent TB infection. Therapy was approved for patients aged 2 years or older who are at high risk for progression to TB disease.[15, 160]

FDA approval for the new indication was partially based on a randomized study of more than 6,000 patients in which a 12-dose, once-weekly regimen of directly observed therapy (DOT) with rifapentine plus isoniazid was compared with a regimen consisting of 9 months of self-administered daily isoniazid. The cumulative rate of tuberculosis disease development was 0.16% in the rifapentine-isoniazid group (5 out of 3074 patients), compared with 0.32% in the isoniazid group (10 out of 3074 patients).[15, 160]

Patients with a clinically significant result on tuberculin skin testing or a positive interferon-gamma release assay (IGRA) result should receive a course of therapy for latent TB once active infection and disease are ruled out. Recommended regimens for latent TB published by the US Centers for Disease Control and Prevention (CDC) are as follows[12, 16] :

Self-administered therapy versus directly observed therapy

A 2017 study reported that self-administered therapy for latent tuberculosis infection (LTBI) may be a viable option for patients when direct medical oversight is unavailable. [161]

As part of an open-label, phase 4 randomized clinical trial, researchers enrolled 1002 patients from outpatient TB clinics in the United States, Spain, Hong Kong, and South Africa between September 2012 and April 2014. Patients with active TB, prior treatment for TB lasting more than 1 week, contact with someone with a resistant form of TB, or prior intolerance to anti-TB agents were excluded. Most enrolled patients (n=774) were in the United States; however, participants were demographically similar between groups. The median age was 36, and 48.1% of the patients were women.

Patients were randomly assigned to receive isoniazid or rifapentine once weekly by directly observed therapy (DOT), self-administered therapy (SAT) with weekly text message reminders, or SAT without reminders. The study's primary objective was to compare treatment adherence, defined as the completion of 11 or more doses of medication within 16 weeks. All participants were counseled on correct pill-taking and symptoms of drug toxicity. All patients had monthly follow-up visits during therapy and 28 days after the last dose to assess adherence and monitor for adverse events.

The researchers documented overall completion rates of 87.2% (95% confidence interval [CI], 83.1%-90.5%) in the DOT group, 74.0% (CI, 68.9%-78.6%) in the SAT group, and 76.4% (CI, 71.3%-80.8%) in the SAT with reminders group.

Specifically, among US patients, the researchers noted treatment completion rates of 85.4% (CI, 80.4%-89.4%), 77.9% (CI, 72.7%-82.6%), and 76.7% (CI, 70.9%-81.7%), respectively. Using a 15% difference to define noninferiority, the researchers found SAT without reminders to be non-inferior to DOT in the United States.

Adverse events were similar among all 3 groups.[161]

Isoniazid plus rifapentine

This combination, approved by the FDA in November 2014, is indicated for patients aged 2 years and older who are at high risk of developing active TB disease (including those in close contact with active TB patients, patients who have had a recent conversion to a positive tuberculin skin test, HIV-infected patients, and those with pulmonary fibrosis on radiograph).

Consider using this 12-dose regimen among populations that are unlikely to complete longer courses of therapy with isoniazid alone. This regimen is not recommended for children under 2 years, individuals who are pregnant or plan to become pregnant, or patients whose TB infection is presumed to be the result of exposure to a person with TB disease that is resistant to 1 of the 2 drugs.

The PREVENT TB Study compared this regimen with 9 months of self-administered, daily isoniazid (300 mg) therapy for latent tuberculosis. The combination therapy was as effective as isoniazid in preventing tuberculosis and had a higher treatment completion rate.[15]

Isoniazid therapy in children

Children younger than 12 years should receive isoniazid for 9 months. In addition, children younger than 5 years who have close contact with a person who has active TB should be started on isoniazid, even if the results of skin testing are negative; preventive therapy can be stopped if the results of repeat skin testing are negative 2-3 months after last contact with a culture-positive source case. Alternatively, children aged 2-11 years may receive DOT with weight-base dosing of once-weekly rifapentine plus isoniazid for 12 weeks.[15, 162]

MDR-TB and patient contacts

Household contacts of patients with MDR-TB have a particularly high risk for tuberculosis, 7.8% within 4 years, in a study from Lima, Peru.[163] Limited data on regimens for treating patients exposed to MDR-TB are available. However, if treatment is initiated, at least 2 drugs should be given, and the index isolate should be susceptible to all drugs used.

Therapy in patients with HIV infection

Recommended regimens in patients with HIV infection include rifampin alone daily for 4 months or isoniazid, daily or twice weekly, for 9 months. Patients on antiretroviral therapy may need rifabutin instead of rifampin because of potential drug interactions.

Prevention and Consultations

The BCG vaccine continues to be used worldwide and usually protects early childhood. Immunity begins to wane, however, as early as 3 months after administration.[164] As previously noted, the BCG vaccine is not recommended in infants in the United States.

In early 2020, Darrah et al reported on the promising efficacy of the BCG vaccine administered intravenously rather than intradermally in macaque monkeys. Intravenous immunization resulted in a significantly more robust T-cell response in lung lymph nodes, blood, spleen, and bronchoalveolar lavage than traditional intradermal immunization. These findings have not been confirmed in human studies.[165]

In a meta-analysis of eight randomized controlled studies involving a total of 10,320 patients aged 15 years or younger, Ayieko et al found that isoniazid prophylaxis reduced the risk of developing TB, with a pooled risk ratio (RR) of 0.65 (P = 0.004). However, isoniazid had no effect in children who initiated treatment at age 4 months or younger. When those patients were excluded, isoniazid prophylaxis reduced the risk of developing TB by 59% (RR, 0.41; P< 0.001).[166]

The public health sector should be notified and involved in cases of TB. Local county health departments are experts and funded in treating TB infection. Consultation with a primary care, pulmonology, internal medicine, or infectious disease specialist before initiating therapy is helpful, and it may be appropriate for this consultant to manage the antituberculous chemotherapy. Consult an expert on MDR-TB in cases of multidrug resistance.

Long-Term Monitoring

After completion of treatment for pulmonary TB, patients remain at risk for late complications, which include relapse, aspergilloma, bronchiectasis, broncholithiasis, fibrothorax, and possibly carcinoma. A copy of the chest radiograph at the time of therapy completion should be provided to the patient to facilitate the diagnosis of late complications.

The relapse rate following appropriate completed therapy is only 0-4% and occurs within the first 2 years after completion. Aspergilloma is a fungus ball that develops in a residual lung abnormality (eg, pneumatocele, bulla, bleb, cyst). It may appear as a crescent sign on chest radiographs. Other superinfections may manifest with an air-fluid level (seen in the image below) and often contain mixed bacteria, including anaerobes.



View Image

Pulmonary tuberculosis with air-fluid level.

Hemoptysis is the most common late complication. Bleeding from submucosal bronchial veins usually is self-limited.

Other complications include the following:

Adverse effects of antibiotic therapy in TB can be severe. They include the following:

Latent Tuberculosis Infection (LTBI) Treatment Guidelines

The National Tuberculosis Controllers Association (NTCA) and Centers for Disease Control and Prevention (CDC) have issued updated treatment guidelines for latent tuberculosis infection (LTBI) among persons who live in the United States.[167]

The recommended 2020 LTBI treatment guidelines include three preferred rifamycin-based regimens and two alternative daily-isoniazid monotherapy regimens. These recommendations are intended for Mycobacterium tuberculosis infections with presumed susceptibility to isoniazid or rifampin. M tuberculosis strains resistant to isoniazid and rifampin are exempt from these recommendations.

Generally, rifamycin-based treatment regimens administered in short courses are preferred over isoniazid monotherapy administered in longer courses for treating LTBI.

Preferred treatment regimens for LTBI

The rifamycin-based preferred regimens for LTBI are as follows:

Prescribing providers or pharmacists should note that rifampin and rifapentine are not interchangeable, and care should be taken to administer the correct medication for the intended regimen.

Alternative treatment regimens for LTBI

The alternative treatment regimens are as follows:

Medication Summary

The treatment of tuberculosis (TB) must satisfy the following basic therapeutic principles:

New cases initially are treated with four drugs: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. After 2 months, they are then treated with a continuation phase of 4 months with isoniazid and rifampin. Patients requiring retreatment initially should receive at least 5 drugs, including isoniazid, rifampin, pyrazinamide, and at least 2 (preferably 3) new drugs to which the patient has not been exposed.[5]  

Shorter versus standard duration of treatment has been explored extensively since approximately 2014. In three phase III trials, shorter TB treatment regimens were less effective than standard 6-month regimens.[168, 169, 170, 171, 172] In all of the trials, one of the standard treatment drugs was replaced with a fluoroquinolone. In the first study, ethambutol was replaced with gatifloxacin for 2 months of intensive treatment followed by a 2-month continuation phase. In the shorter regimen group, 21.0% of patients had unfavorable outcomes, compared with 17.2% in the standard regimen group. Rates of recurrence were 14.6% and 7.1% in the two groups, respectively.[169]

The second study involved a 4-month treatment regimen in which moxifloxacin was substituted for isoniazid for 2 months, followed by moxifloxacin and rifapentine twice weekly for 2 months. This shorter regimen was inferior to a 6-month regimen with moxifloxacin and a standard 6-month treatment regimen.[170]

In the third study, ethambutol or isoniazid was replaced with moxifloxacin. Favorable outcomes were seen in 85% and 80% of the two moxifloxacin groups, compared with 92% of the standard treatment group.[171]

Newer 4-month regimens are being adapted as the data from new clinical trials becomes available. TBTC Study 31/A5349 involved 2516 participants from 34 clinical sites in 13 countries. All patients were AFB smear positive, and 1701 had cavitary lung disease. A 4-month regimen consisting of isoniazid, rifapentine, moxifloxacin, and pyrazinamide was noted to be non-inferior to a standard 6-month regimen of isoniazid, rifampin, pyrazinamide, and ethambutol.[146]  

 

Isoniazid

Clinical Context:  This is the drug of choice for use in preventive therapy and the primary drug for use in combination therapy for active TB. It is also used in combination with rifapentine for adults and children aged 2 years or older with latent TB as once-weekly DOT therapy for 12 weeks. Its mechanism of action is not fully known, but isoniazid may inhibit the synthesis of mycolic acid, resulting in disruption of the bacterial cell wall. In patients receiving treatment for active TB, pyridoxine 25-50 mg orally once daily should be coadministered to prevent peripheral neuropathy.

Rifampin (Rifadin)

Clinical Context:  Rifampin is used in combination with at least 1 other antituberculous drug for the treatment of active TB. It inhibits DNA-dependent RNA polymerase activity in bacterial cells but not in mammalian cells. Cross-resistance may occur.

In most susceptible cases, the patient undergoes 6 months of treatment. Treatment lasts for 9 months if the patient's sputum culture result is still positive after 2 months of therapy.

Rifampin turns body fluids (urine, saliva, tears) orange and it is excreted through bile and enterohepatic circulation. 

Rifampin is a potent inducer of hepatic cytochrome P450 system and decreases the half life of many drugs. 

Pyrazinamide

Clinical Context:  This is a pyrazine analog of nicotinamide that is either bacteriostatic or bactericidal against M tuberculosis, depending on the concentration of drug attained at the site of infection. Pyrazinamide's mechanism of action is unknown. Administer the drug for the initial 2 months of a 6-month or longer treatment regimen for drug-susceptible TB. Treat drug-resistant TB with individualized regimens.

M bovis is uniformly resistant to pyrazinamide. 

Ethambutol (Myambutol)

Clinical Context:  Ethambutol diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). It impairs cell metabolism by inhibiting the synthesis of 1 or more metabolites, which in turn causes cell death. No cross-resistance has been demonstrated.

Mycobacterial resistance is frequent with previous therapy. In such cases, use ethambutol in combination with second-line drugs that have not been previously administered. Administer every 24 hours until permanent bacteriologic conversion and maximal clinical improvement are observed. Absorption is not significantly altered by food.

Adverse effects of ethambutol include optic neuritis, which is usually reversible with discontinuation of the drug. During the period when the patient is on a daily dose of 25 mg/kg, monthly eye exams are recommended.

Streptomycin

Clinical Context:  Streptomycin sulfate, an aminoglycoside, is used for the treatment of susceptible mycobacterial infections. Use this agent in combination with other antituberculous drugs (eg, isoniazid, ethambutol, rifampin).

Although the total period of treatment for TB is a minimum of 6 months, streptomycin therapy is not commonly used for the full duration of therapy, because of toxicity concerns (primarily vestibulotoxicity). The drug is recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.

Levofloxacin (Levaquin)

Clinical Context:  Levofloxacin, a second-line antituberculous drug, is used in combination with rifampin and other antituberculous agents in treating most cases of multidrug-resistant TB (MDR-TB). A good safety profile with long-term use among the fluoroquinolones has made levofloxacin the preferred oral agent for treating MDR-TB caused by organisms resistant to first-line drugs. Levofloxacin elicits its action through inhibition of bacterial topoisomerase IV and DNA gyrase, which are required for DNA replication, transcription, repair, and recombination.

Moxifloxacin (Avelox)

Clinical Context:  Moxifloxacin, a second-line antituberculous drug, inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. Moxifloxacin can be used for MDR-TB caused by organisms known or presumed to be sensitive to fluoroquinolones or when first-line drugs cannot be used because of intolerance.

Rifapentine (Priftin)

Clinical Context:  This agent is used twice weekly as part of a multiple drug regimen for 2 months during the intensive phase of TB treatment, then once weekly for 4 months, along with isoniazid or an appropriate agent for susceptible organisms. It is also indicated for adults and children aged 2 years or older with latent TB in combination with isoniazid as once-weekly therapy for 12 weeks. Rifapentine inhibits DNA-dependent RNA polymerase in susceptible strains of M tuberculosis organisms. It should not be used to treat active tuberculosis in individuals with HIV infection or with positive TB cultures after 2 months of treatment.

Ethionamide (Trecator)

Clinical Context:  Ethionamide is a second-line drug that is bacteriostatic or bactericidal against M tuberculosis, depending on the concentration of the drug attained at the site of infection. It is recommended if treatment with first-line drugs (isoniazid, rifampin) is unsuccessful. Ethionamide can be used to treat any form of active TB. However, it should be used only with other effective antituberculous agents.

Amikacin

Clinical Context:  Amikacin is a second-line drug used to treat patients with MDR-TB or those who do not tolerate first-line therapies. This agent irreversibly binds to the 30S subunit of bacterial ribosomes, blocking the recognition step in protein synthesis and causing growth inhibition.

Cycloserine

Clinical Context:  Cycloserine, a second-line TB drug, inhibits cell wall synthesis in susceptible strains of gram-positive and gram-negative bacteria and in M tuberculosis. It is a structural analogue of D-alanine, which antagonizes the role of D-alanine in bacterial cell wall synthesis, inhibiting growth. Like all antituberculosis drugs, cycloserine should be administered in conjunction with other effective TB drugs and not as the sole therapeutic agent

Capreomycin (Capastat)

Clinical Context:  Capreomycin, which is obtained from Streptomyces capreolus, is a second-line drug that is coadministered with other antituberculous agents in pulmonary infections caused by capreomycin-susceptible strains of M tuberculosis. Capreomycin is used only when first-line agents (eg, isoniazid, rifampin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli.

Rifabutin (Mycobutin)

Clinical Context:  This is an ansamycin antibiotic derived from rifamycin S. Rifabutin inhibits DNA-dependent RNA polymerase, preventing chain initiation. It is used for TB treatment in individuals on specific HIV medications, when rifampin is contraindicated (most protease inhibitors).

Clofazimine (Lamprene)

Clinical Context:  Clofazimine inhibits mycobacterial growth, binding preferentially to mycobacterial DNA. It has antimicrobial properties, but its mechanism of action is unknown. It is rarely used to treat MDR-TB. Like all drugs for TB, clofazimine is always used with other antituberculous agents. Clofazimine is available only on a single-patient basis, to physicians who submit an Investigational New Drug (IND) application to the US Food and Drug Administration (FDA).

Para-aminosalicylic acid (Paser)

Clinical Context:  This is a bacteriostatic agent that is useful as a second-line agent against M tuberculosis. It is most commonly used for MDR-TB or when therapy with isoniazid or rifampin is not possible. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. Administer this agent with other antituberculous drugs.

Bedaquiline (Sirturo)

Clinical Context:  Bedaquiline is a diarylquinoline that inhibits mycobacterial adenosine 5'-triphosphate (ATP) synthase, an enzyme essential for the generation of energy in Mycobacterium tuberculosis.. Therapy with bedaquiline is reserved for use when an effective treatment regimen cannot otherwise be provided. It is not indicated to treat latent, extrapulmonary, or drug-sensitive tuberculosis.

Pretomanid

Clinical Context:  Nitroimidazooxazine that kills actively replicating M tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production. It is indicated as part of a combination regimen with bedaquiline and linezolid for treatment pulmonary extensively drug-resistant TB (XDR-TB) or treatment-intolerant or nonresponsive MDR-TB in adults.

Delamanid

Clinical Context:  Delamanid is a dihydro-nitroimidazooxazole derivative. It acts by inhibiting the synthesis of mycobacterial cell wall. The 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment has a conditional recommendation that delamanid may be included in the treatment of patients with MDR/rifampin-resistant (RR)-TB aged >3 years on longer regimens.

Class Summary

The goals of TB treatment are to shorten the clinical course of TB, prevent complications, prevent the development of latency and/or subsequent recurrences, and decrease the likelihood of TB transmission. In patients with latent TB, the goal of therapy is to prevent disease progression.

What is tuberculosis (TB) (consumption)?What are the signs and symptoms of pulmonary tuberculosis (TB) (consumption)?What are the symptoms of tuberculous (TB) meningitis?What are the symptoms of skeletal tuberculosis (TB)?What are the symptoms of genitourinary tuberculosis (TB)?What are the symptoms of gastrointestinal tuberculosis (TB)?What are the physical findings of pulmonary tuberculosis (TB) (consumption)?What are the signs and symptoms of extrapulmonary tuberculosis (TB)?Does the absence of significant physical findings exclude active tuberculosis (TB) (consumption)?Which tests are used to screen for tuberculosis (TB) (consumption)?Which lab tests should be performed in suspected tuberculosis (TB)?Which tests are performed to determine drug susceptibility following a positive culture for tuberculosis (TB) (consumption)?Which radiography findings are diagnostic for tuberculosis (TB) (consumption)?Which tests should be performed in the diagnosis of extrapulmonary tuberculosis (TB)?Which infection prevention and control measures should be implemented for patients with active tuberculosis (TB) (consumption)?What is the initial pharmacologic therapy for tuberculosis (TB) (consumption)?How is tuberculosis (TB) treated in pregnant women?How is tuberculosis (TB) treated in children?How is tuberculosis (TB) treated in patients with HIV infection and AIDS?What are the treatment options for multidrug-resistant tuberculosis (MDR-TB)?Which surgical interventions are indicated for multidrug-resistant tuberculosis (MDR-TB)?What are the CDC treatment recommendations for latent tuberculosis infection (LTBI)?What is the global burden of tuberculosis (TB) (consumption)?Which comorbidity has contributed to the emergence and spread of drug-resistant tuberculosis (TB)?Which infectious agent causes tuberculosis (TB) (consumption)?What is the most common site for the development of tuberculosis (TB)?What is the primary screening test for tuberculosis (TB) infection?What is the usual treatment regimen for tuberculosis (TB) (consumption)?What are the typical communicable-disease control laws for tuberculosis (TB)?What is the early history of tuberculosis (TB) (consumption)?What caused the historical increase in the global prevalence of tuberculosis (TB) (consumption)?What caused a resurgence of tuberculosis (TB) in the 1980s in the US?What is the prevalence of coinfection with tuberculosis (TB) and HIV infection/AIDS?Where is tuberculosis (TB) most prevalent and what factors have contributed to its spread?What is multidrug-resistant tuberculosis (MDR-TB)?Which factors contribute to the high prevalence of multidrug-resistant tuberculosis (MDR-TB)?What is the global proportion of multidrug-resistant tuberculosis (MDR-TB) cases?What population group has the highest rate of resistant tuberculosis (MDR-TB) in the US?What is the prevalence of extensively drug-resistant tuberculosis (XDR-TB) in the US?What is the cure rate for multidrug-resistant tuberculosis (MDR-TB)?Is directly observed therapy (DOT) effective in reducing the incidence of multidrug-resistant tuberculosis (MDR-TB)?Is there a standard triage protocol for treatment of tuberculosis (TB) in the emergency department (ED)?Which emergency department (ED) patients are at increased risk for active tuberculosis (TB)?What is the incidence of extrapulmonary tuberculosis (EPTB)?What is the prevalence of cutaneous tuberculosis (TB)?Which physical findings suggest ocular tuberculosis (TB)?What are the symptoms of ocular tuberculosis (TB)?What is the incidence of ocular tuberculosis (TB)?Where can patients find information on tuberculosis (TB)?How does M tuberculosis infection occur?What causes the antigenicity of mycobacteria in tuberculosis (TB)?What is the pathogenesis of latent tuberculosis infection (LTBI)?What is the most common site for the development of tuberculosis (TB)?What are the most common sites of extrapulmonary tuberculosis (TB)?What is the principal cause of tissue destruction due to M tuberculosis infection?What is the pathogenesis of tuberculosis (TB)-related uveitis?What is the pathogenesis of tuberculosis (TB) lesions?What are the features of early tubercles in tuberculosis (TB)?What is the disease course of tuberculosis (TB) lesions?What inhibits the growth of tubercle bacillus in tuberculosis (TB)?What is the disease course in hosts unable to arrest the initial infection of tuberculosis (TB)?How do lesions initially develop in tuberculosis (TB)?How do proliferative lesions develop in tuberculosis (TB)?How do exudative lesions develop in tuberculosis (TB)?What is the etiology of tuberculosis (TB)?What are the characteristics of Mycobacterium tuberculosis (M tuberculosis)?How is Mycobacterium tuberculosis transmitted?How frequently does exposure to Mycobacterium tuberculosis result in active tuberculosis (TB)?In the US, what percentage of tuberculosis (TB) is caused by reactivation of latent infection?Does isoniazid-resistant tuberculosis (TB) have higher or lower transmissibility than fully-susceptible TB?How does Mycobacterium tuberculosis spread to extrapulmonary sites?Which groups are at increased risk for developing disseminated (primary miliary) tuberculosis (TB)?Which factors determine the transmissibility of Mycobacterium tuberculosis infection?Which settings increase the risk for transmission of Mycobacterium tuberculosis infection?Which factors increase an individual&#39;s risk of acquiring active tuberculosis (TB)?Which medications significantly increase the risk for tuberculosis (TB)?Does immunosuppressive therapy increase the risk for tuberculosis (TB)?What are the possible complications of tuberculosis (TB) in children younger than 5 years?Do children with tuberculosis (TB) commonly infect other children?Are there genetic factors related to tuberculosis (TB)?What role does the NRAMP1 gene have in tuberculosis (TB)?What role does the SP110 gene have in tuberculosis (TB)?What role does the CISH gene have in tuberculosis (TB)?What role does the IRGM gene have in tuberculosis (TB)?What role does the IFNG gene have in tuberculosis (TB)?What role does the IFNGR1 gene have in tuberculosis (TB)?What role does the TIRAP gene have in tuberculosis (TB)?What role does the CD209 gene have in tuberculosis (TB)?What is the incidence of tuberculosis (TB) in the US?Which groups have the highest incidence of tuberculosis (TB) in the US?What is the racial predilection of tuberculosis (TB) in the US?How many deaths occur annually from tuberculosis (TB) in the US?What is the global prevalence of tuberculosis (TB)?What trends have been identified by the WHO in the global disease burden of tuberculosis (TB)?Which countries make up the majority of the global incidence of tuberculosis (TB)?How does the incidence of tuberculosis (TB) vary among foreign-born and native-born minorities in the US?Does the incidence of tuberculosis (TB) differ between men and women?Does the incidence of tuberculosis (TB) vary among different age groups?What is the prognosis of tuberculosis (TB) (consumption)?What are the poor prognostic markers of tuberculosis (TB)?Which factors increase the risk of developing tuberculosis (TB) (consumption)?What are classic features of active pulmonary tuberculosis (TB) (consumption)?What is the presentation of tuberculosis (TB) (consumption) in elderly individuals?What are the signs and symptoms of extrapulmonary tuberculosis (TB)?What is the presentation of tuberculous (TB) meningitis?What are the signs and symptoms of skeletal tuberculosis (TB)?What are the signs and symptoms of genitourinary tuberculosis (TB)?What are the signs and symptoms of GI tuberculosis (TB)?Which physical findings suggest tuberculosis (TB) (consumption)?Which physical findings suggest extrapulmonary tuberculosis (TB)?Which physical findings suggest lymphadenopathy in tuberculosis (TB)?Does the absence of any significant physical findings exclude active tuberculosis (TB)?Which conditions should be included in the differential diagnosis of pulmonary tuberculosis (TB)?Which conditions should be included in the differential diagnosis of extrapulmonary tuberculosis (TB)?Which conditions should be included in the differential diagnosis of cutaneous tuberculosis (TB)?What are the differential diagnoses for Tuberculosis (TB)?Which tests are used to screen for tuberculosis (TB) infection?Which lab tests are performed in suspected tuberculosis (TB)?What is the role of acid-fast bacilli (AFB) staining in the diagnosis of tuberculosis (TB)?When are imaging studies indicated in the diagnosis of tuberculosis (TB)?What is the role of technetium-99m (99m Tc) methoxy isobutyl isonitrile SPECT scanning in the diagnosis of tuberculosis (TB)?Is radiography useful in the diagnosis of multidrug-resistant tuberculosis (MDR-TB)?Which tests are used to diagnose extrapulmonary tuberculosis (TB)?Which factors make ocular tuberculosis (TB) especially difficult to diagnose?What is the histopathology of extrapulmonary tuberculosis (TB)?Which symptoms suggest tuberculous (TB) meningitis or tuberculoma, and what tests are performed to confirm diagnosis?Which testing is needed when vertebral (Pott disease) or brain involvement is suspected in tuberculosis (TB)?When are urinalysis and urine cultures indicated in the diagnosis of tuberculosis (TB)?Which tests should be performed if tuberculosis (TB) is suspected during pregnancy?Which diagnostic tests are indicated for suspected congenital tuberculosis (TB)?How is postnatal tuberculosis (TB) in infants contracted?Which chest radiographic findings may suggest tuberculosis (TB) in children?When is HIV testing indicated in patients with tuberculosis (TB)?Among HIV-positive patients, who is at increased risk for developing tuberculosis (TB)?Which tuberculosis (TB) screening test should be performed prior to initiation of antiretroviral therapy (ART) in patients with HIV infection?Which tests should be performed in patients with tuberculosis (TB) and HIV infection?What are the increased health risks for patients with tuberculosis (TB) and HIV infection?What is the role of a sputum smear in the diagnosis of tuberculosis (TB)?How are sputum samples collected in patients with suspected tuberculosis (TB)?What is the role of Ziehl-Neelsen staining in the diagnosis of tuberculosis (TB)?How often are culture-positive specimens associated with a negative smear result for tuberculosis (TB)?What can be used to differentiate tuberculosis (TB) with negative sputum smears from latent TB infection (LTBI)?What is the role of nucleic acid amplification tests (NAAT) in the diagnosis of tuberculosis (TB)?What are the CDC recommendations for use of nucleic acid amplifications in the diagnosis of pulmonary tuberculosis (TB)?How accurate is nucleic acid amplification testing (NAAT) in diagnosing tuberculosis (TB)?Which test is the most specific for tuberculosis (TB)?What is the role of acid-fast bacilli (AFB) cultures in the diagnosis of tuberculosis (TB)?Are broth cultures available for use in clinical labs for the diagnosis of tuberculosis (TB)?What is the role of blood cultures in the diagnosis of tuberculosis (TB)?When is drug susceptibility testing indicated in the diagnosis of tuberculosis (TB)?What is the efficacy of DNA sequencing analysis for detecting drug-resistant tuberculosis (TB)?What is the efficacy of automated molecular testing for the detection of tuberculosis (TB)?What is the role of microscopic-observation drug susceptibility (MODS) and thin-layer agar (TLA) assays in the diagnosis of multidrug-resistant tuberculosis (MDR-TB)?Which rapid drug susceptibility tests are used to diagnose multidrug-resistant tuberculosis (MDR-TB)?)?What is the role of chest radiography in the diagnosis of tuberculosis (TB)?When is chest radiography used to screen for sarcoidosis in patients with suspected tuberculosis (TB)?Which chest radiography findings suggest tuberculosis (TB)?In a symptomatic patient with normal chest radiographic findings, is tuberculosis (TB) excluded?How do radiographic findings differentiate primary tuberculosis (TB) from reactivation TB?Which chest radiographic findings suggest reactivation tuberculosis (TB)?Which chest radiographic findings suggest tuberculosis (TB) with HIV infection?Which chest radiographic findings suggest healed tuberculosis (TB)?Which chest radiographic findings suggest miliary tuberculosis (TB)?Which chest radiographic findings suggest pleural tuberculosis (TB)?What is the primary screening test for tuberculosis (TB) infection?How is the Mantoux tuberculin skin test with purified protein derivative (PPD) administered in patients with suspected tuberculosis (TB)?What are the population-based criteria for purified protein derivative (PPD) positivity in tuberculosis (TB) testing?What are the population-based criteria for purified protein derivative (PPD) positivity in tuberculosis (TB) testing for patients who have received the Bacillus Calmette–Guérin (BCG) vaccine?What is the role of interferon-gamma release assay (IGRA) in the diagnosis of tuberculosis (TB)?Are interferon-gamma release assays (IGRA) effective for the diagnosis of tuberculosis (TB)?What are the advantages and disadvantages of interferon-gamma release assays (IGRA)?What is the accuracy of tuberculin skin testing and interferon-gamma release assay (IGRA) for tuberculosis (TB) infection?What are the highest positive and negative likelihood ratios for latent tuberculosis infection (LTBI)?How accurate is skin testing in predicting the subsequent development of tuberculosis (TB)?Which tests may be more reliable than skin testing for identifying patients who will progress to active tuberculosis (TB)?Which infection prevention and control measures should be implemented for patients with active tuberculosis (TB) (consumption)?What is the initial empiric treatment of tuberculosis (TB)?What baseline assessments are required for patients with tuberculosis (TB) who receive pyrazinamide or long-term ethambutol therapy?How long should drug therapy for tuberculosis (TB) be continued?When is directly observed therapy (DOT) indicated in the treatment of tuberculosis (TB)?How should active tuberculosis (TB) be monitored?What is the treatment for patients with tuberculosis (TB) who are actively seizing or who have overdosed on antimycobacterial medication?How should pregnant women with active tuberculosis (TB) be treated?When is preventive treatment for tuberculosis (TB) recommended in women who are pregnant?What are the risks of isoniazid therapy in pregnant and postpartum women with tuberculosis (TB)?Should women breastfeed during preventive therapy for tuberculosis (TB)?Does tuberculosis during pregnancy increase the risk of preterm birth?How is tuberculosis (TB) treated in children?What is the duration of treatment for postnatal tuberculosis (TB)?How is isoniazid administered in the treatment of tuberculosis (TB) in children?How is rifampin administered in the treatment of tuberculosis (TB) in children?What is the role of bedaquiline in the treatment of tuberculosis (TB) in children? What is the role of ethambutol in the treatment of tuberculosis (TB) in children?How does the treatment regimen for tuberculosis (TB) differ in patients with HIV infection?What is immune reconstitution inflammatory syndrome (IRIS) in patients receiving treatment for tuberculosis (TB) and HIV infection?What are the benefits of early antiretroviral therapy (ART) in patients with HIV infection and tuberculosis (TB)?What is the treatment length and recurrence rate of treatment for tuberculosis (TB) in patients with HIV infection?Which medication reduces complications in the treatment of tuberculous meningitis?What is the treatment for tuberculosis (TB) that is resistant to a single drug?Is rifapentine (Priftin) an effective treatment for latent tuberculosis infection (LTBI)?What are the CDC guidelines for the treatment of latent tuberculosis infection (LTBI)?How effective is self-administered therapy versus directly observed therapy in the treatment of latent tuberculosis infection (LTBI)?How is isoniazid plus rifapentine administered in the treatment of latent tuberculosis infection (LTBI)?When are longer isoniazid plus rifapentine regimens indicated in the treatment of latent tuberculosis infection (LTBI)?When are isoniazid plus rifapentine regimens contraindicated in the treatment of latent tuberculosis infection (LTBI)?How does combination isoniazid plus rifapentine therapy compare to isoniazid alone for treatment of latent tuberculosis infection (LTBI)?Should children with latent tuberculosis infection (LTBI) receive isoniazid therapy?When is treatment indicated for individuals exposed to multidrug-resistant tuberculosis (MDR-TB)?What is the recommended treatment for patients with HIV infection and latent tuberculosis infection (LTBI)?Does the Bacillus Calmette–Guérin (BCG) vaccine offer protection against tuberculosis (TB)?Does isoniazid prophylaxis reduce the risk of tuberculosis (TB) in children?Which specialist consultations are indicated in the treatment of tuberculosis (TB)?What are the possible post-treatment complications of tuberculosis (TB)?What is the relapse rate in patients who have completed therapy for tuberculosis (TB)?What are the most common post-treatment complications of tuberculosis (TB)?What are the adverse effects of antibiotic therapy in tuberculosis (TB)?When is treatment initiated when multidrug-resistant tuberculosis (MDR-TB) is suspected?Which medications are used for the treatment of multidrug-resistant tuberculosis (MDR-TB)?Which factors increase the likelihood of successful multidrug-resistant tuberculosis (MDR-TB) treatment?How long should treatment be continued for multidrug-resistant tuberculosis (MDR-TB)?Is bedaquiline (Sirturo) effective for the treatment of multidrug-resistant tuberculosis (MDR-TB)?What are the CDC guidelines for the use of bedaquiline in the treatment of multidrug-resistant tuberculosis (MDR-TB)?How is the diagnosis of extensively drug-resistant tuberculosis (XDR-TB) established?According to the CDC, which groups have the highest risk for pyrazinamide-resistant tuberculosis (TB)?When is surgical resection of an infected lung indicated in the treatment of multidrug-resistant tuberculosis (MDR-TB)?What are the possible complications of surgical resection in multidrug-resistant tuberculosis (MDR-TB)?What are the basic therapeutic principles for the treatment of tuberculosis (TB)?What is the initial treatment of new cases of tuberculosis (TB)?What is the efficacy of shorter tuberculosis (TB) drug regimens compared to standard 6-month regimens?Which medications in the drug class Antitubercular agents are used in the treatment of Tuberculosis (TB)?

Author

Syeda Sahra, MD, Fellow, Department of Medicine, Section of Infectious Diseases, Oklahoma University of Health Sciences Center

Disclosure: Nothing to disclose.

Coauthor(s)

Maria Alkozah, MD, MPH, Assistant Professor of Medicine, University of Oklahoma College of Medicine; Faculty, Section of Infectious Diseases, Department of Medicine, Medical Director for Antimicrobial Stewardship, Medical Director for the Outpatient Antimicrobial Therapy Program, University of Oklahoma Medical Center

Disclosure: Nothing to disclose.

Nelson Ivan Agudelo Higuita, MD, DTM&H, CTH®, Edith Kinney Gaylor Presidential Professor, Associate Professor, Program Director, Infectious Diseases Fellowship Program, Medical Director, Refugee and Travel Clinic, Department of Medicine, Section of Infectious Diseases, University of Oklahoma Health Sciences Center; Attending Physician, Infectious Diseases Consultation Service, Department of General Internal Medicine, Oklahoma University Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Additional Contributors

Judith K Amorosa, MD, FACR, Clinical Professor of Radiology and Vice Chair for Faculty Development and Medical Education, Rutgers Robert Wood Johnson Medical School

Disclosure: Nothing to disclose.

Thomas E Herchline, MD, Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical Consultant, Public Health, Dayton and Montgomery County (Ohio) Tuberculosis Clinic

Disclosure: Received research grant from: Regeneron.

Acknowledgements

Erica Bang State University of New York Downstate Medical Center College of Medicine

Disclosure: Nothing to disclose.

Diana Brainard, MD Consulting Staff, Department of Infectious Disease, Massachusetts General Hospital

Disclosure: Nothing to disclose.

Pamela S Chavis, MD Professor, Department of Ophthalmology and Neurosciences, Medical University of South Carolina College of Medicine

Pamela S Chavis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Ophthalmology, and North American Neuro-Ophthalmology Society

Disclosure: Nothing to disclose.

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Theodore J Gaeta, DO, MPH, FACEP Clinical Associate Professor, Department of Emergency Medicine, Weill Cornell Medical College; Vice Chairman and Program Director of Emergency Medicine Residency Program, Department of Emergency Medicine, New York Methodist Hospital; Academic Chair, Adjunct Professor, Department of Emergency Medicine, St George's University School of Medicine

Theodore J Gaeta, DO, MPH, FACEP is a member of the following medical societies: Alliance for Clinical Education, American College of Emergency Physicians, Clerkship Directors in Emergency Medicine, Council of Emergency Medicine Residency Directors, New York Academy of Medicine, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Aaron Glatt, MD Professor of Clinical Medicine, New York Medical College; President and CEO, Former Chief Medical Officer, Departments of Medicine and Infectious Diseases, St Joseph Hospital (formerly New Island Hospital)

Aaron Glatt, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society for Microbiology, American Thoracic Society, American Venereal Disease Association, Infectious Diseases Society of America, International AIDS Society, and SocietyforHealthcareEpidemiology of America

Disclosure: Nothing to disclose.

Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology

Disclosure: Nothing to disclose.

John M Leedom, MD Professor Emeritus of Medicine, Keck School of Medicine of the University of Southern California

John M Leedom, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society for Microbiology, Infectious Diseases Society of America, International AIDS Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

James Li, MD Former Assistant Professor, Division of Emergency Medicine, Harvard Medical School; Board of Directors, Remote Medicine

Disclosure: Nothing to disclose.

Jeffrey Meffert, MD Assistant Clinical Professor of Dermatology, University of Texas School of Medicine at San Antonio

Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society

Disclosure: Nothing to disclose.

Monte S Meltzer, MD Chief, Dermatology Service, Union Memorial Hospital

Monte S Meltzer, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Susannah K Mistr, MD Resident Physician, Department of Ophthalmology, University of Maryland Medical Center

Susannah K Mistr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, American Medical Association, American Medical Student Association/Foundation, American Society of Cataract and Refractive Surgery, and South Carolina Medical Association

Disclosure: Nothing to disclose.

Carol A Nacy, PhD Adjunct Professor, Department of Biology, Catholic University of America; Adjunct Professor, Department of Tropical Medicine and Microbiology, George Washington University

Carol A Nacy, PhD is a member of the following medical societies: American Academy of Microbiology and American Society for Microbiology

Disclosure: Sequella, Inc. Ownership interest Employment; Sequella, Inc. Ownership interest investor

J James Rowsey, MD Former Director of Corneal Services, St Luke's Cataract and Laser Institute

J James Rowsey, MD is a member of the following medical societies: American Academy of Ophthalmology, American Association for the Advancement of Science, American Medical Association, Association for Research in Vision and Ophthalmology, Florida Medical Association, Pan-American Association of Ophthalmology, Sigma Xi, and Southern Medical Association

Disclosure: Nothing to disclose.

Hampton Roy Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

John D Sheppard Jr, MD, MMSc Professor of Ophthalmology, Microbiology and Molecular Biology, Clinical Director, Thomas R Lee Center for Ocular Pharmacology, Ophthalmology Residency Research Program Director, Eastern Virginia Medical School; President, Virginia Eye Consultants

John D Sheppard Jr, MD, MMSc is a member of the following medical societies: American Academy of Ophthalmology, American Society for Microbiology, American Society of Cataract and Refractive Surgery, American Uveitis Society, and Association for Research in Vision and Ophthalmology

Disclosure: Nothing to disclose.

Richard H Sinert, DO Professor of Emergency Medicine, Clinical Assistant Professor of Medicine, Research Director, State University of New York College of Medicine; Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center

Richard H Sinert, DO is a member of the following medical societies: American College of Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Keith Tsang, MD Resident Physician, Clinical Assistant Instructor, Department of Emergency Medicine, State University of New York Downstate, Kings County Hospital

Keith Tsang, MD is a member of the following medical societies: American College of Emergency Physicians, Emergency Medicine Residents Association, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Shyam Verma, MBBS, DVD, FAAD Clinical Associate Professor, Department of Dermatology, University of Virginia; Adjunct Associate Professor, Department of Dermatology, State University of New York at Stonybrook, Adjunct Associate Professor, Department of Dermatology, University of Pennsylvania

Shyam Verma, MBBS, DVD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Eric L Weiss, MD, DTM&H Medical Director, Office of Service Continuity and Disaster Planning, Fellowship Director, Stanford University Medical Center Disaster Medicine Fellowship, Chairman, SUMC and LPCH Bioterrorism and Emergency Preparedness Task Force, Clinical Associate Progressor, Department of Surgery (Emergency Medicine), Stanford University Medical Center

Eric L Weiss, MD, DTM&H is a member of the following medical societies: American College of Emergency Physicians, American College of Occupational and Environmental Medicine, American Medical Association, American Society of Tropical Medicine and Hygiene, Physicians for Social Responsibility, Southeastern Surgical Congress, Southern Association for Oncology, Southern Clinical Neurological Society, and Wilderness Medical Society

Disclosure: Nothing to disclose.

References

  1. WHO. Tuberculosis. World Health Organization. Available at https://www.who.int/news-room/fact-sheets/detail/tuberculosis. October 29, 2024; Accessed: October 30, 2024.
  2. Nardell EA. Mycobacteria. Porter RE. The Merck Manual of Diagnosis and Therapy. Rahway, NJ: Merck & Co Inc; Reviewed/Revised July 2022.
  3. Chakinala RC, Khatri AM. Gastrointestinal Tuberculosis. StatPearls. 2024 Jan. [View Abstract]
  4. Brehm TT, Terhalle E. [Extrapulmonary tuberculosis]. Dtsch Med Wochenschr. 2023 Sep. 148 (19):1242-1249. [View Abstract]
  5. [Guideline] Treatment of tuberculosis. MMWR Recomm Rep. 2003 Jun 20. 52:1-77. [View Abstract]
  6. Swaminathan S, Narendran G, Venkatesan P, et al. Efficacy of a 6-month versus 9-month intermittent treatment regimen in HIV-infected patients with tuberculosis: a randomized clinical trial. Am J Respir Crit Care Med. 2010 Apr 1. 181(7):743-51. [View Abstract]
  7. CDC. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis. CDC. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/tb/TB_HIV_Drugs/default.htm. Accessed: 07/05/2023.
  8. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010 Feb 25. 362(8):697-706. [View Abstract]
  9. Torok ME, Farrar JJ. When to start antiretroviral therapy in HIV-associated tuberculosis. N Engl J Med. 2011 Oct 20. 365(16):1538-40. [View Abstract]
  10. Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, et al. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. Am J Respir Crit Care Med. 2019 Nov 15. 200 (10):e93-e142. [View Abstract]
  11. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. 2019.
  12. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep. 2000 Jun 9. 49:1-51. [View Abstract]
  13. Menzies D, Adjobimey M, Ruslami R, et al. Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults. N Engl J Med. 2018 Aug 2. 379 (5):440-453. [View Abstract]
  14. Diallo T, Adjobimey M, Ruslami R, et al. Safety and Side Effects of Rifampin versus Isoniazid in Children. N Engl J Med. 2018 Aug 2. 379 (5):454-463. [View Abstract]
  15. Sterling TR, Villarino ME, Borisov AS, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011 Dec 8. 365(23):2155-66. [View Abstract]
  16. Borisov AS, Bamrah Morris S, Njie GJ, Winston CA, Burton D, Goldberg S, et al. Update of Recommendations for Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent Mycobacterium tuberculosis Infection. MMWR Morb Mortal Wkly Rep. 2018 Jun 29. 67 (25):723-726. [View Abstract]
  17. Tuberculosis. https://www.who.int/news-room/fact-sheets/detail/tuberculosis. Available at https://www.who.int/news-room/fact-sheets/detail/tuberculosis. April 21, 2023; Accessed: September 25, 2023.
  18. Wells CD, Cegielski JP, Nelson LJ, et al. HIV infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis. 2007 Aug 15. 196 Suppl 1:S86-107. [View Abstract]
  19. Moreira J, Fochesatto JB, Moreira AL, Pereira M, Porto N, Hochhegger B. Tuberculous pneumonia: a study of 59 microbiologically confirmed cases. J Bras Pneumol. 2011 Mar-Apr. 1. [View Abstract]
  20. John Bernardo, MD. Epidemiology and pathology of miliary and extrapulmonary tuberculosis. Available at https://medilib.ir/uptodate/show/8029. Sep 2023.; Accessed: Nov, 2023.
  21. Nyamathi A, Salem BE, Shin SS, Jones AA, Garfin DR, Yadav K, et al. Effect of a Nurse-Led Community Health Worker Intervention on Latent Tuberculosis Medication Completion Among Homeless Adults. Nurs Res. 2021 Nov-Dec 01. 2-3. [View Abstract]
  22. Guzman K, Crowder R, Leddy A, Maraba N, Jennings L, Ahmed S, et al. Acceptability and feasibility of digital adherence technologies for drug-susceptible tuberculosis treatment supervision: A meta-analysis of implementation feedback. PLOS Digit Health. 2023 Aug 15. [View Abstract]
  23. Roguin A. Rene Theophile Hyacinthe Laënnec (1781-1826): the man behind the stethoscope. Clin Med Res. 2006 Sep. [View Abstract]
  24. Tubiana M. [Wilhelm Conrad Röntgen and the discovery of X-rays]. Bull Acad Natl Med. 1996 Jan. 180 (1):97-108. [View Abstract]
  25. Trends in Tuberculosis, 2021. https://www.cdc.gov/tb/publications/factsheets/statistics/tbtrends.htm. Available at https://www.cdc.gov/tb/publications/factsheets/statistics/tbtrends.htm. November 9, 2022; Accessed: 10/03/2023.
  26. Tuberculosis and HIV. https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/hiv/treatment/tuberculosis-hiv. Available at https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/hiv/treatment/tuberculosis-hiv. 2023; Accessed: 9/29/2023.
  27. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City--turning the tide. N Engl J Med. 1995 Jul 27. 333 (4):229-33. [View Abstract]
  28. Myra A. Montalbano Carol M. Knowles Deborah A. Adams Patsy A. Hall Robert F. Fagan Karl A. Brendel Harry R. Holden Gerald F. Jones Division of Public Health Surveillance and Informatics Epidemiology Program Office. Summary of Notifiable Diseases, United States 1996. MMWR. Ocr 31, 1997. Available at https://www.cdc.gov/mmwr/preview/mmwrhtml/00050719.htm
  29. Ritacco V, Di Lonardo M, Reniero A, Ambroggi M, Barrera L, Dambrosi A, et al. Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis. 1997 Sep. 176 (3):637-42. [View Abstract]
  30. From the Centers for Disease Control and Prevention. Tuberculosis treatment interruptions--Ivanovo Oblast, Russian Federation, 1999. JAMA. 2001 Apr 18. 285 (15):1953-4. [View Abstract]
  31. Selwyn PA, Hartel D, Lewis VA, Schoenbaum EE, Vermund SH, Klein RS, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med. 1989 Mar 2. 320 (9):545-50. [View Abstract]
  32. WHO. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update. World Health Organization. Available at http://www.who.int/tb/challenges/mdr/tdrfaqs/en/index.html. December 15, 2022; Accessed: July 5, 2023.
  33. Raviglione MC. Tuberculosis. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 20e. McGraw Hill; 2018. McGraw Hill.;
  34. Mlambo CK, Warren RM, Poswa X, Victor TC, Duse AG, Marais E. Genotypic diversity of extensively drug-resistant tuberculosis (XDR-TB) in South Africa. Int J Tuberc Lung Dis. 2008 Jan. 12(1):99-104. [View Abstract]
  35. Global Tuberculosis Programme. Global tuberculosis report 2020. October 14, 2020. Available at https://www.who.int/publications/i/item/9789240013131
  36. Hogan AB, Jewell BL, Sherrard-Smith E, Vesga JF,et al. Potential impact of the COVID-19 pandemic on HIV, tuberculosis, and malaria in low-income and middle-income countries: a modelling study. Lancet Glob Health. 2020 Sep. 8 (9):e1132-e1141. [View Abstract]
  37. Global Tuberculosis Programme. Global tuberculosis report 2020. 14 October 2020. Available at https://www.who.int/publications/i/item/9789240013131
  38. CDC. Plan to combat extensively drug-resistant tuberculosis: recommendations of the Federal Tuberculosis Task Force. MMWR Recomm Rep. 2009 Feb 13. 58:1-43. [View Abstract]
  39. Sokolove PE, Lee BS, Krawczyk JA, et al. Implementation of an emergency department triage procedure for the detection and isolation of patients with active pulmonary tuberculosis. Ann Emerg Med. 2000 Apr. 35(4):327-36. [View Abstract]
  40. Moran GJ, McCabe F, Morgan MT, Talan DA. Delayed recognition and infection control for tuberculosis patients in the emergency department. Ann Emerg Med. 1995 Sep. 26(3):290-5. [View Abstract]
  41. Menzies D, Joshi R, Pai M. Risk of tuberculosis infection and disease associated with work in health care settings. Int J Tuberc Lung Dis. 2007 Jun. 11(6):593-605. [View Abstract]
  42. Chen Q, Chen W, Hao F. Cutaneous tuberculosis: A great imitator. Clin Dermatol. 2019 May-Jun. 37 (3):192-199. [View Abstract]
  43. Bates B, Crowell EL. Ophthalmic manifestations of tuberculosis. Curr Opin Ophthalmol. 2023 Nov 1. 34 (6):529-534. [View Abstract]
  44. Patel SS, Saraiya NV, Tessler HH, Goldstein DA. Mycobacterial ocular inflammation: delay in diagnosis and other factors impacting morbidity. JAMA Ophthalmol. 2013 Jun. 131 (6):752-8. [View Abstract]
  45. WHO. Leading health agencies outline updated terminology for pathogens that transmit through the air. World Health Organization. Available at https://www.who.int/news/item/18-04-2024-leading-health-agencies-outline-updated-terminology-for-pathogens-that-transmit-through-the-air. April 18, 2024; Accessed: April 25, 2024.
  46. Pfyffer, G. E. 2007. Mycobacterium: general characteristics, laboratory detection, and staining procedures. P. R. Murray, E. J. Baron, J. H. Jorgensen, M. L. Landry, and M. A. Pfaller (ed.), Manual of clinical microbiology, 9th ed. ASM Press, Washington, DC; 1: 543-572.
  47. Daniel W. Fitzgerald, Timothy R. Sterling and David W. Haas. Mycobacterium tuberculosis. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th. Elsevier; June 6, 2021. 2985-3021.
  48. Russell DG. Mycobacterium tuberculosis and the intimate discourse of a chronic infection. Immunol Rev. 2011 Mar. 240 (1):252-68. [View Abstract]
  49. Wolf AJ, Desvignes L, Linas B, Banaiee N, Tamura T, Takatsu K, et al. Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs. J Exp Med. 2008 Jan 21. 205 (1):105-15. [View Abstract]
  50. Ramakrishnan L. Revisiting the role of the granuloma in tuberculosis. Nat Rev Immunol. 2012 Apr 20. 12 (5):352-66. [View Abstract]
  51. Pagán AJ, Ramakrishnan L. Immunity and Immunopathology in the Tuberculous Granuloma. Cold Spring Harb Perspect Med. 2014 Nov 6. 5 (9):[View Abstract]
  52. Lenaerts A, Barry CE 3rd, Dartois V. Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses. Immunol Rev. 2015 Mar. 264 (1):288-307. [View Abstract]
  53. Mattila JT, Ojo OO, Kepka-Lenhart D, Marino S, Kim JH, Eum SY, et al. Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. J Immunol. 2013 Jul 15. 191 (2):773-84. [View Abstract]
  54. Lin PL, Ford CB, Coleman MT, Myers AJ, Gawande R, Ioerger T, et al. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med. 2014 Jan. 20 (1):75-9. [View Abstract]
  55. Lin PL, Flynn JL. The End of the Binary Era: Revisiting the Spectrum of Tuberculosis. J Immunol. 2018 Nov 1. 201 (9):2541-2548. [View Abstract]
  56. Volkman HE, Pozos TC, Zheng J, Davis JM, Rawls JF, Ramakrishnan L. Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science. 2010 Jan 22. 327 (5964):466-9. [View Abstract]
  57. Ravn P, Demissie A, Eguale T, Wondwosson H, Lein D, Amoudy HA, et al. Human T cell responses to the ESAT-6 antigen from Mycobacterium tuberculosis. J Infect Dis. 1999 Mar. 179 (3):637-45. [View Abstract]
  58. Sheen P, O'Kane CM, Chaudhary K, Tovar M, Santillan C, Sosa J, et al. High MMP-9 activity characterises pleural tuberculosis correlating with granuloma formation. Eur Respir J. 2009 Jan. 33 (1):134-41. [View Abstract]
  59. Peyron P, Vaubourgeix J, Poquet Y, Levillain F, Botanch C, Bardou F, et al. Foamy macrophages from tuberculous patients' granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence. PLoS Pathog. 2008 Nov. 4 (11):e1000204. [View Abstract]
  60. Singh V, Jamwal S, Jain R, Verma P, Gokhale R, Rao KV. Mycobacterium tuberculosis-driven targeted recalibration of macrophage lipid homeostasis promotes the foamy phenotype. Cell Host Microbe. 2012 Nov 15. 12 (5):669-81. [View Abstract]
  61. Russell DG, Cardona PJ, Kim MJ, Allain S, Altare F. Foamy macrophages and the progression of the human tuberculosis granuloma. Nat Immunol. 2009 Sep. 10 (9):943-8. [View Abstract]
  62. Davis JM, Ramakrishnan L. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell. 2009 Jan 9. 136 (1):37-49. [View Abstract]
  63. Schreiber HA, Harding JS, Hunt O, Altamirano CJ, Hulseberg PD, Stewart D, et al. Inflammatory dendritic cells migrate in and out of transplanted chronic mycobacterial granulomas in mice. J Clin Invest. 2011 Oct. 121 (10):3902-13. [View Abstract]
  64. Elkington PT, Ugarte-Gil CA, Friedland JS. Matrix metalloproteinases in tuberculosis. Eur Respir J. 2011 Aug. 38 (2):456-64. [View Abstract]
  65. Palaci M, Dietze R, Hadad DJ, Ribeiro FK, Peres RL, Vinhas SA, et al. Cavitary disease and quantitative sputum bacillary load in cases of pulmonary tuberculosis. J Clin Microbiol. 2007 Dec. 45 (12):4064-6. [View Abstract]
  66. Canetti G. Present aspects of bacterial resistance in tuberculosis. Am Rev Respir Dis. 1965 Nov. 92 (5):687-703. [View Abstract]
  67. Coleman MT, Chen RY, Lee M, Lin PL, Dodd LE, Maiello P, et al. PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis. Sci Transl Med. 2014 Dec 3. 6 (265):265ra167. [View Abstract]
  68. Prosser G, Brandenburg J, Reiling N, Barry CE 3rd, Wilkinson RJ, Wilkinson KA. The bacillary and macrophage response to hypoxia in tuberculosis and the consequences for T cell antigen recognition. Microbes Infect. 2017 Mar. 19 (3):177-192. [View Abstract]
  69. Simmons JD, Stein CM, Seshadri C, Campo M, Alter G, Fortune S, et al. Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection. Nat Rev Immunol. 2018 Sep. 18 (9):575-589. [View Abstract]
  70. Rangaka MX, Wilkinson KA, Glynn JR, Ling D, Menzies D, Mwansa-Kambafwile J, et al. Predictive value of interferon-γ release assays for incident active tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2012 Jan. 12 (1):45-55. [View Abstract]
  71. Pai M, Behr MA, Dowdy D, Dheda K, Divangahi M, Boehme CC, et al. Tuberculosis. Nat Rev Dis Primers. 2016 Oct 27. 2:16076. [View Abstract]
  72. Abrahams KA, Besra GS. Mycobacterial cell wall biosynthesis: a multifaceted antibiotic target. Parasitology. 2018 Feb. 145 (2):116-133. [View Abstract]
  73. Verhagen LM, van den Hof S, van Deutekom H, et al. Mycobacterial factors relevant for transmission of tuberculosis. J Infect Dis. 2011 May. 203(9):1249-55. [View Abstract]
  74. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001 Oct 11. 345(15):1098-104. [View Abstract]
  75. Brassard P, Suissa S, Kezouh A, Ernst P. Inhaled Corticosteroids and Risk of Tuberculosis in Patients with Respiratory Diseases. Am J Respir Crit Care Med. 2010 Oct 1. [View Abstract]
  76. Aravindan PP. Host genetics and tuberculosis: Theory of genetic polymorphism and tuberculosis. Lung India. 2019 May-Jun. 36 (3):244-252. [View Abstract]
  77. Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med. 1998 Mar 5. 338(10):640-4. [View Abstract]
  78. Cervino AC, Lakiss S, Sow O, Hill AV. Allelic association between the NRAMP1 gene and susceptibility to tuberculosis in Guinea-Conakry. Ann Hum Genet. 2000 Nov. 64:507-12. [View Abstract]
  79. Searle S, Blackwell JM. Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility. J Med Genet. 1999 Apr. 36(4):295-9. [View Abstract]
  80. Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med. 1998 Mar 5. 338 (10):640-4. [View Abstract]
  81. Shaw MA, Collins A, Peacock CS, Miller EN, Black GF, Sibthorpe D, et al. Evidence that genetic susceptibility to Mycobacterium tuberculosis in a Brazilian population is under oligogenic control: linkage study of the candidate genes NRAMP1 and TNFA. Tuber Lung Dis. 1997. 78 (1):35-45. [View Abstract]
  82. Druszczyńska M, Strapagiel D, Kwiatkowska S, Kowalewicz-Kulbat M, Rózalska B, Chmiela M, et al. Tuberculosis bacilli still posing a threat. Polymorphism of genes regulating anti-mycobacterial properties of macrophages. Pol J Microbiol. 2006. 55 (1):7-12. [View Abstract]
  83. Saunders BM, Britton WJ. Life and death in the granuloma: immunopathology of tuberculosis. Immunol Cell Biol. 2007 Feb-Mar. 85 (2):103-11. [View Abstract]
  84. Nadesalingam J, Dodds AW, Reid KB, Palaniyar N. Mannose-binding lectin recognizes peptidoglycan via the N-acetyl glucosamine moiety, and inhibits ligand-induced proinflammatory effect and promotes chemokine production by macrophages. J Immunol. 2005 Aug 1. 175 (3):1785-94. [View Abstract]
  85. LeBouder E, Rey-Nores JE, Rushmere NK, Grigorov M, Lawn SD, Affolter M, et al. Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk. J Immunol. 2003 Dec 15. 171 (12):6680-9. [View Abstract]
  86. Intemann CD, Thye T, Niemann S, et al. Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains. PLoS Pathog. 2009 Sep. 5(9):e1000577. [View Abstract]
  87. King KY, Lew JD, Ha NP, Lin JS, Ma X, Graviss EA, et al. Polymorphic allele of human IRGM1 is associated with susceptibility to tuberculosis in African Americans. PLoS One. 2011 Jan 21. 6 (1):e16317. [View Abstract]
  88. Chan J, Flynn J. The immunological aspects of latency in tuberculosis. Clin Immunol. 2004 Jan. 110 (1):2-12. [View Abstract]
  89. Chackerian AA, Alt JM, Perera TV, Dascher CC, Behar SM. Dissemination of Mycobacterium tuberculosis is influenced by host factors and precedes the initiation of T-cell immunity. Infect Immun. 2002 Aug. 70 (8):4501-9. [View Abstract]
  90. Rossouw M, Nel HJ, Cooke GS, van Helden PD, Hoal EG. Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene. Lancet. 2003 May 31. 361(9372):1871-2. [View Abstract]
  91. Levin M, Newport MJ, D'Souza S, et al. Familial disseminated atypical mycobacterial infection in childhood: a human mycobacterial susceptibility gene?. Lancet. 1995 Jan 14. 345(8942):79-83. [View Abstract]
  92. Newport MJ, Huxley CM, Huston S, et al. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. 1996 Dec 26. 335(26):1941-9. [View Abstract]
  93. Khor CC, Chapman SJ, Vannberg FO, Dunne A, Murphy C, Ling EY, et al. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet. 2007 Apr. 39 (4):523-8. [View Abstract]
  94. Barreiro LB, Neyrolles O, Babb CL, et al. Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis. PLoS Med. 2006 Feb. 3(2):e20. [View Abstract]
  95. Tuberculosis-Data and Statistics. www.cdc.gov. Available at https://www.cdc.gov/tb/statistics/default.htm. 03/23/2023; Accessed: 10/25/2023.
  96. Reported TB in the US, 2021 Surveillance Report. https://www.cdc.gov/tb/statistics/reports/2021/demographics.htm. Available at https://www.cdc.gov/tb/statistics/reports/2021/demographics.htm. November 29, 2022; Accessed: 10/25/2023.
  97. Cox HS, Morrow M, Deutschmann PW. Long term efficacy of DOTS regimens for tuberculosis: systematic review. BMJ. 2008 Mar 1. 336(7642):484-7. [View Abstract]
  98. Jasmer RM, Bozeman L, Schwartzman K, et al. Recurrent tuberculosis in the United States and Canada: relapse or reinfection?. Am J Respir Crit Care Med. 2004 Dec 15. 170(12):1360-6. [View Abstract]
  99. van Rie A, Warren R, Richardson M, et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med. 1999 Oct 14. 341(16):1174-9. [View Abstract]
  100. Waitt CJ, Peter K Banda N, White SA, et al. Early deaths during tuberculosis treatment are associated with depressed innate responses, bacterial infection, and tuberculosis progression. J Infect Dis. 2011 Aug. 204(3):358-62. [View Abstract]
  101. Yoo SD, Cattamanchi A, Den Boon S, Worodria W, Kisembo H, Huang L, et al. Clinical significance of normal chest radiographs among HIV-seropositive patients with suspected tuberculosis in Uganda. Respirology. 2011 Jul. 16 (5):836-41. [View Abstract]
  102. Palmieri F, Girardi E, Pellicelli AM, Rianda A, Bordi E, Rizzi EB, et al. Pulmonary tuberculosis in HIV-infected patients presenting with normal chest radiograph and negative sputum smear. Infection. 2002 Apr. 30 (2):68-74. [View Abstract]
  103. Sossen B, Richards AS, Heinsohn T, Frascella B, Balzarini F, Oradini-Alacreu A, et al. The natural history of untreated pulmonary tuberculosis in adults: a systematic review and meta-analysis. Lancet Respir Med. 2023 Apr. 11 (4):367-379. [View Abstract]
  104. ROPER WH, WARING JJ. Primary serofibrinous pleural effusion in military personnel. Am Rev Tuberc. 1955 May. 71 (5):616-34. [View Abstract]
  105. BIEHL JP. Miliary tuberculosis; a review of sixty-eight adult patients admitted to a municipal general hospital. Am Rev Tuberc. 1958 Apr. 77 (4):605-22. [View Abstract]
  106. Maartens G, Willcox PA, Benatar SR. Miliary tuberculosis: rapid diagnosis, hematologic abnormalities, and outcome in 109 treated adults. Am J Med. 1990 Sep. 89 (3):291-6. [View Abstract]
  107. Roth BJ. Searching for tuberculosis in the pleural space. Chest. 1999 Jul. 116 (1):3-5. [View Abstract]
  108. Diacon AH, Van de Wal BW, Wyser C, Smedema JP, Bezuidenhout J, Bolliger CT, et al. Diagnostic tools in tuberculous pleurisy: a direct comparative study. Eur Respir J. 2003 Oct. 22 (4):589-91. [View Abstract]
  109. Garg RK, Malhotra HS, Gupta R. Spinal cord involvement in tuberculous meningitis. Spinal Cord. 2015 Sep. 53 (9):649-57. [View Abstract]
  110. Erdem H, Ozturk-Engin D, Tireli H, Kilicoglu G,et al. Hamsi scoring in the prediction of unfavorable outcomes from tuberculous meningitis: results of Haydarpasa-II study. J Neurol. 2015. 262 (4):890-8. [View Abstract]
  111. Linares LF, Valcarcel A, Mesa Del Castillo J, Saiz E, Bermudez A, Castellon P. Tuberculous arthritis with multiple joint involvement. J Rheumatol. 1991 Apr. 18 (4):635-6. [View Abstract]
  112. Saltzman SJ, Feigin RD. Tuberculous otitis media and mastoiditis. J Pediatr. 1971 Dec. 79 (6):1004-6. [View Abstract]
  113. Bruschini L, Ciabotti A, Berrettini S. Chronic Tuberculous Otomastoiditis: A Case Report. J Int Adv Otol. 2016 Aug. 12 (2):219-221. [View Abstract]
  114. Sebastian SK, Singhal A, Sharma A, Doloi P. Tuberculous otitis media -series of 10 cases. J Otol. 2020 Sep. 15 (3):95-98. [View Abstract]
  115. Mazurek GH, Jereb J, Lobue P, Iademarco MF, Metchock B, Vernon A. Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR Recomm Rep. 2005 Dec 16. 54:49-55. [View Abstract]
  116. Ang M, Htoon HM, Chee SP. Diagnosis of tuberculous uveitis: clinical application of an interferon-gamma release assay. Ophthalmology. 2009 Jul. 116(7):1391-6. [View Abstract]
  117. Schuurmans MM, Ellmann A, Bouma H, Diacon AH, Dyckmans K, Bolliger CT. Solitary pulmonary nodule evaluation with 99mTc-methoxy isobutyl isonitrile in a tuberculosis-endemic area. Eur Respir J. 2007 Dec. 30(6):1090-5. [View Abstract]
  118. Sonnenberg P, Glynn JR, Fielding K, Murray J, Godfrey-Faussett P, Shearer S. How soon after infection with HIV does the risk of tuberculosis start to increase? A retrospective cohort study in South African gold miners. J Infect Dis. 2005 Jan 15. 191(2):150-8. [View Abstract]
  119. Muga R, Ferreros I, Langohr K, et al. Changes in the incidence of tuberculosis in a cohort of HIV-seroconverters before and after the introduction of HAART. AIDS. 2007 Nov 30. 21(18):2521-7. [View Abstract]
  120. Sterling TR, Lau B, Zhang J, et al. Risk Factors for Tuberculosis After Highly Active Antiretroviral Therapy Initiation in the United States and Canada: Implications for Tuberculosis Screening. J Infect Dis. 2011 Sep. 204(6):893-901. [View Abstract]
  121. Bassett IV, Wang B, Chetty S, et al. Intensive tuberculosis screening for HIV-infected patients starting antiretroviral therapy in Durban, South Africa. Clin Infect Dis. 2010 Oct 1. 51(7):823-9. [View Abstract]
  122. [Guideline] Jensen PA, Lambert LA, Iademarco MF, Ridzon R. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Recomm Rep. 2005 Dec 30. 54:1-141. [View Abstract]
  123. Brown M, Varia H, Bassett P, Davidson RN, Wall R, Pasvol G. Prospective study of sputum induction, gastric washing, and bronchoalveolar lavage for the diagnosis of pulmonary tuberculosis in patients who are unable to expectorate. Clin Infect Dis. 2007 Jun 1. 44(11):1415-20. [View Abstract]
  124. Jafari C, Thijsen S, Sotgiu G, et al. Bronchoalveolar lavage enzyme-linked immunospot for a rapid diagnosis of tuberculosis: a Tuberculosis Network European Trialsgroup study. Am J Respir Crit Care Med. 2009 Oct 1. 180(7):666-73. [View Abstract]
  125. Tan SH, Tan BH, Goh CL, et al. Detection of Mycobacterium tuberculosis DNA using polymerase chain reaction in cutaneous tuberculosis and tuberculids. Int J Dermatol. 1999 Feb. 38(2):122-7. [View Abstract]
  126. Vieites B, Suarez-Penaranda JM, Perez Del Molino ML, et al. Recovery of Mycobacterium tuberculosis DNA in biopsies of erythema induratum--results in a series of patients using an improved polymerase chain reaction technique. Br J Dermatol. 2005 Jun. 152(6):1394-6. [View Abstract]
  127. [Guideline] Updated guidelines for the use of nucleic acid amplification tests in the diagnosis of tuberculosis. MMWR Morb Mortal Wkly Rep. 2009 Jan 16. 58(1):7-10. [View Abstract]
  128. Reuters Health Information. Direct nucleic acid amplification testing improves TB diagnosis. Medscape Medical News. June 6, 2013.
  129. Marks SM, Cronin W, Venkatappa T, et al. The Health-System Benefits and Cost-effectiveness of Using Mycobacterium Tuberculosis Direct Nucleic Acid Amplification Testing to Diagnose Tuberculosis Disease in the United States. Clin Infect Dis. 2013 May 22. [View Abstract]
  130. Badak FZ, Kiska DL, Setterquist S, et al. Comparison of mycobacteria growth indicator tube with BACTEC 460 for detection and recovery of mycobacteria from clinical specimens. J Clin Microbiol. 1996 Sep. 34(9):2236-9. [View Abstract]
  131. Choi JH, Lee KW, Kang HR, et al. Clinical efficacy of direct DNA sequencing analysis on sputum specimens for early detection of drug-resistant Mycobacterium tuberculosis in a clinical setting. Chest. 2010 Feb. 137(2):393-400. [View Abstract]
  132. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010 Sep 9. 363(11):1005-15. [View Abstract]
  133. Boehme CC, Nicol MP, Nabeta P, et al. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet. 2011 Apr 30. 377(9776):1495-505. [View Abstract]
  134. Minion J, Leung E, Menzies D, Pai M. Microscopic-observation drug susceptibility and thin layer agar assays for the detection of drug resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2010 Oct. 10(10):688-98. [View Abstract]
  135. CDC. Classification of Tuberculin Skin Reactions. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/tb/publications/LTBI/diagnosis.htm#3. Accessed: July 5, 2023.
  136. [Guideline] Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection - United States, 2010. MMWR Recomm Rep. 2010 Jun 25. 59:1-25. [View Abstract]
  137. Manuel O, Humar A, Preiksaitis J, et al. Comparison of quantiferon-TB gold with tuberculin skin test for detecting latent tuberculosis infection prior to liver transplantation. Am J Transplant. 2007 Dec. 7(12):2797-801. [View Abstract]
  138. Mazurek GH, Weis SE, Moonan PK, et al. Prospective comparison of the tuberculin skin test and 2 whole-blood interferon-gamma release assays in persons with suspected tuberculosis. Clin Infect Dis. 2007 Oct 1. 45(7):837-45. [View Abstract]
  139. Chang KC, Leung CC. Systematic review of interferon-gamma release assays in tuberculosis: focus on likelihood ratios. Thorax. 2010 Mar. 65(3):271-6. [View Abstract]
  140. Leung CC, Yam WC, Yew WW, et al. T-Spot.TB outperforms tuberculin skin test in predicting tuberculosis disease. Am J Respir Crit Care Med. 2010 Sep 15. 182(6):834-40. [View Abstract]
  141. Diel R, Loddenkemper R, Niemann S, Meywald-Walter K, Nienhaus A. Negative and positive predictive value of a whole-blood interferon-? release assay for developing active tuberculosis: an update. Am J Respir Crit Care Med. 2011 Jan 1. 183(1):88-95. [View Abstract]
  142. Kim SH, Lee SO, Park JB, et al. A prospective longitudinal study evaluating the usefulness of a T-cell-based assay for latent tuberculosis infection in kidney transplant recipients. Am J Transplant. 2011 Sep. 11(9):1927-35. [View Abstract]
  143. Donald PR, Schaaf HS, Gie RP, Beyers N, Sirgel FA, Venter A. Stool microscopy and culture to assist the diagnosis of pulmonary tuberculosis in childhood. J Trop Pediatr. 1996 Oct. 42 (5):311-2. [View Abstract]
  144. MacLean E, Sulis G, Denkinger CM, Johnston JC, Pai M, Ahmad Khan F. Diagnostic Accuracy of Stool Xpert MTB/RIF for Detection of Pulmonary Tuberculosis in Children: a Systematic Review and Meta-analysis. J Clin Microbiol. 2019 Jun. 57 (6):[View Abstract]
  145. Kokuto H, Sasaki Y, Yoshimatsu S, Mizuno K, Yi L, Mitarai S. Detection of Mycobacterium tuberculosis (MTB) in Fecal Specimens From Adults Diagnosed With Pulmonary Tuberculosis Using the Xpert MTB/Rifampicin Test. Open Forum Infect Dis. 2015 Apr. 2 (2):ofv074. [View Abstract]
  146. Dorman SE, Nahid P, Kurbatova EV, Goldberg SV, Bozeman L et sl. High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial. Contemp Clin Trials. 2020 Mar. 90:105938. [View Abstract]
  147. Lin HC, Lin HC, Chen SF. Increased risk of low birthweight and small for gestational age infants among women with tuberculosis. BJOG. 2010 Apr. 117(5):585-90. [View Abstract]
  148. Donovan J, Bang ND, Imran D, Nghia HDT, Burhan E, Huong DTT et al. Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults. N Engl J Med. 2023 Oct 12. 389 (15):1357-1367. [View Abstract]
  149. Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 2018. 2019.
  150. Kurbatova EV, Cavanaugh JS, Dalton T, Click E, Cegielski JP. Epidemiology of pyrazinamide-resistant tuberculosis in the United States, 1999-2009. Clin Infect Dis. 2013 Jul 9. [View Abstract]
  151. Boggs W. Increasing Prevalence of Pyrazinamide-Resistant Tuberculosis. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/808192. Accessed: July 29, 2013.
  152. Sirturo (bedaquiline) prescribing information [package insert]. Titusville, NJ: Janssen Therapeutics, Division of Johnson & Johnson. December, 2012. Available at
  153. Tucker ME. FDA approves bedaquiline for resistant TB treatment. Medscape Medical News. Dec 31, 2012. Medscape. Available at http://www.medscape.com/viewarticle/776901. Accessed: July 5, 2023.
  154. Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009 Jun 4. 360(23):2397-405. [View Abstract]
  155. Achar J, Hewison C, Cavalheiro AP, Skrahina A, Cajazeiro J, Nargiza P, et al. Off-Label Use of Bedaquiline in Children and Adolescents with Multidrug-Resistant Tuberculosis. Emerg Infect Dis. 2017 Oct. 23 (10):1711-1713. [View Abstract]
  156. CDC. Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR Recomm Rep. 2013 Oct 25. 62:1-12. [View Abstract]
  157. Barclay L. MDR TB: CDC Issues Guidelines for Use of New Drug. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/813151. Accessed: July 5, 2023.
  158. Conradie F, Diacon AH, Everitt D, Mendel C, van Niekerk C, Howell P, et al. The NIX-TB trial of pretomanid, bedaquiline and linezolid to treat XDR TB. Presented at the Conference on Retroviruses and Opportunistic Infections (CROI) 2017. Seattle, Washington. February 15, 2017.
  159. Pretomanid [package insert]. Hyderabad, India: Mylan (for TB Alliance). August, 2019. Available at
  160. Sanofi Receives FDA Approval of Priftin® (Rifapentine) Tablets for the Treatment of Latent Tuberculosis Infection. Available at http://en.sanofi.com/Images/37707_20141202_priftin_en.pdf. Accessed: Dec 10 2014.
  161. Belknap R, Holland D, Feng PJ, Millet JP, Caylà JA, Martinson NA, et al. Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection: A Randomized Trial. Ann Intern Med. 2017 Nov 7. [View Abstract]
  162. CDC. Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR. 2011;60:1650-1653.
  163. Becerra MC, Appleton SC, Franke MF, et al. Tuberculosis burden in households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study. Lancet. 2011 Jan 8. 377(9760):147-52. [View Abstract]
  164. Weir RE, Gorak-Stolinska P, Floyd S, et al. Persistence of the immune response induced by BCG vaccination. BMC Infect Dis. 2008 Jan 25. 8:9. [View Abstract]
  165. Darrah PA, Zeppa JJ, Maiello P, et al. Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature. 2020 Jan. 577 (7788):95-102. [View Abstract]
  166. Ayieko J, Abuogi L, Simchowitz B, Bukusi EA, Smith AH, Reingold A. Efficacy of isoniazid prophylactic therapy in prevention of tuberculosis in children: a meta-analysis. BMC Infect Dis. 2014 Feb 20. 14:91. [View Abstract]
  167. [Guideline] Sterling TR, Njie G, Zenner D, Cohn DL, Reves R, Ahmed A, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep. 2020 Feb 14. 69 (1):1-11. [View Abstract]
  168. Hackethal V. Short TB Therapies Fail in Larger, Longer Trials. Medscape Medical News. Available at http://www.medscape.com/viewarticle/833799. Accessed: July 5, 2023.
  169. Merle CS, Fielding K, Sow OB, et al. A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med. 2014 Oct 23. 371(17):1588-98. [View Abstract]
  170. Jindani A, Harrison TS, Nunn AJ, et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med. 2014 Oct 23. 371(17):1599-608. [View Abstract]
  171. Gillespie SH, Crook AM, McHugh TD, et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 2014 Oct 23. 371(17):1577-87. [View Abstract]
  172. Warner DF, Mizrahi V. Shortening treatment for tuberculosis--to basics. N Engl J Med. 2014 Oct 23. 371(17):1642-3. [View Abstract]
  173. Burman WJ, Goldberg S, Johnson JL, et al. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med. 2006 Aug 1. 174(3):331-8. [View Abstract]
  174. World Health Organization. Antituberculosis drug resistance in the world. The WHO/IUATLD global project on anti-tuberculosis drug resistance surveillance WHO. Geneva. 2008. 1-120.
  175. CDC. CDC. Trends in Tuberculosis – United States, 2011. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6111a2.htm?s_cid=mm6111a2_w. Accessed: July 5, 2023.
  176. Leung CC, Lam TH, Chan WM, et al. Lower risk of tuberculosis in obesity. Arch Intern Med. 2007 Jun 25. 167(12):1297-304. [View Abstract]
  177. Slama K, Chiang CY, Enarson DA, et al. Tobacco and tuberculosis: a qualitative systematic review and meta-analysis. Int J Tuberc Lung Dis. 2007 Oct. 11(10):1049-61. [View Abstract]
  178. Tosh K, Campbell SJ, Fielding K, et al. Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa. Proc Natl Acad Sci U S A. 2006 Jul 5. 103(27):10364-8. [View Abstract]
  179. Khor CC, Vannberg FO, Chapman SJ, et al. CISH and susceptibility to infectious diseases. N Engl J Med. 2010 Jun 3. 362(22):2092-101. [View Abstract]
  180. Khor CC, Chapman SJ, Vannberg FO, et al. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet. 2007 Apr. 39(4):523-8. [View Abstract]
  181. CDC. Tuberculosis (TB). Data and Statistics. Available at http://www.cdc.gov/tb/statistics/default.htm. March 23, 2023; Accessed: July 5, 2023.
  182. WHO. Global tuberulosis control 2008: surveillance, planning, financing. World Health Organization. Available at http://www.who.int/topics/tuberculosis/en/. Accessed: July 5, 2023.
  183. Xu P, Chen H, Xu J, Wu M, Zhu X, Wang F, et al. Moxifloxacin is an effective and safe candidate agent for the tuberculosis treatment: a meta-analysis. Int J Infect Dis. 2015 Oct 16. [View Abstract]
  184. History of World TB Day. https://www.cdc.gov/tb/worldtbday/history.htm. Available at https://www.cdc.gov/tb/worldtbday/history.htm. February 15, 2023; Accessed: September 25, 2023.
  185. Patterson B, Morrow C, Singh V, Moosa A, Gqada M, Woodward J, et al. Detection of Mycobacterium tuberculosis bacilli in bio-aerosols from untreated TB patients. Gates Open Res. 2017. 1:11. [View Abstract]
  186. Lin PL, Ford CB, Coleman MT, Myers AJ, Gawande R, Ioerger T, et al. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med. 2014 Jan. 20 (1):75-9. [View Abstract]
  187. Irwin SM, Prideaux B, Lyon ER, Zimmerman MD, Brooks EJ, Schrupp CA, et al. Bedaquiline and Pyrazinamide Treatment Responses Are Affected by Pulmonary Lesion Heterogeneity in Mycobacterium tuberculosis Infected C3HeB/FeJ Mice. ACS Infect Dis. 2016 Apr 8. 2 (4):251-267. [View Abstract]
  188. Barberis I, Bragazzi NL, Galluzzo L, Martini M. The history of tuberculosis: from the first historical records to the isolation of Koch's bacillus. J Prev Med Hyg. 2017 Mar. 58 (1):E9-E12. [View Abstract]
  189. Epstein DM, Kline LR, Albelda SM, Miller WT. Tuberculous pleural effusions. Chest. 1987 Jan. 91 (1):106-9. [View Abstract]
  190. Mukwenha S, Dzinamarira T, Mugurungi O, Musuka G. Maintaining robust HIV and tuberculosis services in the COVID-19 era: A public health dilemma in Zimbabwe. Int J Infect Dis. 2020 Nov. 100:394-395. [View Abstract]
  191. Global Tuberculosis Programme. Global tuberculosis report 2021. Available at https://www.who.int/publications/i/item/9789240037021
  192. Moro ML, Gori A, Errante I, Infuso A, Franzetti F, Sodano L, et al. An outbreak of multidrug-resistant tuberculosis involving HIV-infected patients of two hospitals in Milan, Italy. Italian Multidrug-Resistant Tuberculosis Outbreak Study Group. AIDS. 1998 Jun 18. 12 (9):1095-102. [View Abstract]

Anteroposterior chest radiograph of a young patient who presented to the emergency department (ED) with cough and malaise. The radiograph shows a classic posterior segment right upper lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine (remotemedicine.org).

Under a high magnification of 15549x, this scanning electron micrograph depicts some of the ultrastructural details seen in the cell wall configuration of a number of Gram-positive Mycobacterium tuberculosis bacteria. As an obligate aerobic organism, M. tuberculosis can only survive in an environment containing oxygen. This bacterium ranges in length between 2-4 microns, with a width between 0.2-0.5 microns. Image courtesy of the Centers for Disease Control and Prevention/Dr. Ray Butler.

Acid-fast bacillus smear showing characteristic cording in Mycobacterium tuberculosis.

Axial noncontrast enhanced computed tomography with pulmonary window shows a cavity with an irregular wall in the right apex of a 37-year-old man who presented with cough and fever (same patient as above).

Coronal reconstructed computed tomography image shows the right apical cavity in a 37-year-old man who presented with cough and fever (same patient as above).

Axial chest computed tomography without intravenous contrast with pulmonary window setting shows a right apical thick-walled cavity and surrounding lung consolidation in a 43-year-old man who presented with cough and fever (same patient as above).

Coronal reconstructed computed tomography image shows the consolidated, partially collapsed right upper lobe with a cavity that is directly connected to a bronchus in a 43-year-old man who presented with cough and fever (same patient as above).

Axial chest computed tomography without intravenous contrast with pulmonary window setting through the mid-chest shows a large, irregular-walled cavity with nodules and air-fluid level and two smaller cavities in a 43-year-old man who presented with cough and hemoptysis (same patient as above). Small, patchy peripheral opacities are also present in the left lower lobe. In the right mid-lung, nodular opacities are in a tree-in-bud distribution, suggestive of endobronchial spread.

Coronal reconstructed computed tomography image shows the lingular cavity with irregular nodules and right mid-lung nodular opacities in a 43-year-old man who presented with cough and hemoptysis (same patient as above).

This radiograph shows a patient with typical radiographic findings of tuberculosis.

Anteroposterior chest radiograph of a young patient who presented to the emergency department (ED) with cough and malaise. The radiograph shows a classic posterior segment right upper lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine (remotemedicine.org).

Lateral chest radiograph of a patient with posterior segment right upper lobe density consistent with active tuberculosis. Image courtesy of Remote Medicine (remotemedicine.org).

This chest radiograph shows asymmetry in the first costochondral junctions of a 37-year-old man who presented with cough and fever. Further clarification with computed tomography is needed.

This posteroanterior chest radiograph shows right upper lobe consolidation with minimal volume loss (elevated horizontal fissure) and a cavity in a 43-year-old man who presented with cough and fever.

The posteroanterior chest radiograph shows a large cavity with surrounding consolidation in the lingular portion of the left upper lobe in a 43-year-old man who presented with cough and hemoptysis. There are also a few nodular opacities in the right mid-lung zone.

Pulmonary tuberculosis with air-fluid level.

Acid-fast bacillus smear showing characteristic cording in Mycobacterium tuberculosis.

This radiograph shows a patient with typical radiographic findings of tuberculosis.

This is a chest radiograph taken after therapy was administered to a patient with tuberculosis.

Anteroposterior chest radiograph of a young patient who presented to the emergency department (ED) with cough and malaise. The radiograph shows a classic posterior segment right upper lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine (remotemedicine.org).

Lateral chest radiograph of a patient with posterior segment right upper lobe density consistent with active tuberculosis. Image courtesy of Remote Medicine (remotemedicine.org).

Pulmonary tuberculosis with air-fluid level.

Under a high magnification of 15549x, this scanning electron micrograph depicts some of the ultrastructural details seen in the cell wall configuration of a number of Gram-positive Mycobacterium tuberculosis bacteria. As an obligate aerobic organism, M. tuberculosis can only survive in an environment containing oxygen. This bacterium ranges in length between 2-4 microns, with a width between 0.2-0.5 microns. Image courtesy of the Centers for Disease Control and Prevention/Dr. Ray Butler.

Numerous acid-fast bacilli (pink) from a bronchial wash are shown on a high-power oil immersion.

Necrotizing granuloma due to tuberculosis shown on low-power hematoxylin and eosin stain. There is central caseous necrosis and a multinucleated giant cell in the central left. Mixed inflammation is seen in the background.

This chest radiograph shows asymmetry in the first costochondral junctions of a 37-year-old man who presented with cough and fever. Further clarification with computed tomography is needed.

Axial noncontrast enhanced computed tomography with pulmonary window shows a cavity with an irregular wall in the right apex of a 37-year-old man who presented with cough and fever (same patient as above).

Coronal reconstructed computed tomography image shows the right apical cavity in a 37-year-old man who presented with cough and fever (same patient as above).

This posteroanterior chest radiograph shows right upper lobe consolidation with minimal volume loss (elevated horizontal fissure) and a cavity in a 43-year-old man who presented with cough and fever.

Axial chest computed tomography without intravenous contrast with pulmonary window setting shows a right apical thick-walled cavity and surrounding lung consolidation in a 43-year-old man who presented with cough and fever (same patient as above).

Coronal reconstructed computed tomography image shows the consolidated, partially collapsed right upper lobe with a cavity that is directly connected to a bronchus in a 43-year-old man who presented with cough and fever (same patient as above).

The posteroanterior chest radiograph shows a large cavity with surrounding consolidation in the lingular portion of the left upper lobe in a 43-year-old man who presented with cough and hemoptysis. There are also a few nodular opacities in the right mid-lung zone.

Axial chest computed tomography without intravenous contrast with pulmonary window setting through the mid-chest shows a large, irregular-walled cavity with nodules and air-fluid level and two smaller cavities in a 43-year-old man who presented with cough and hemoptysis (same patient as above). Small, patchy peripheral opacities are also present in the left lower lobe. In the right mid-lung, nodular opacities are in a tree-in-bud distribution, suggestive of endobronchial spread.

Coronal reconstructed computed tomography image shows the lingular cavity with irregular nodules and right mid-lung nodular opacities in a 43-year-old man who presented with cough and hemoptysis (same patient as above).