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Tuberculosis Overview

Tuberculosis (TB) is an ancient disease that has been linked back to civilizations thousands of years ago. Hippocrates was among the first to describe the manifestations of the disease, and Aristotle believed it to be contagious. It was not until 1882 that the actual tubercle bacillus was first described by Robert Koch.3859 

At the start of the 20th century in Western society, TB was the leading cause of death.3907  The Centers for Disease Control and Prevention (CDC), a part of the Department of Health and Human Services (DHHS), has a Division of Tuberculosis Elimination that collects information on newly reported cases of TB in the United States. Since 1993, the CDC has provided trends and highlights from data collected through the National Tuberculosis Surveillance System.3864 

Etiology of Tuberculosis

An initial TB infection (primary TB) occurs when TB-containing material is inhaled, usually when an indivdual is exposed to a TB-infected individual who is coughing or sneezing. Reactivation may occur at a later stage and will be described later in this section. Primary TB begins when an inhaled unit of 1 to 3 bacilli is ingested by an alveolar macrophage. Because of the ventilatory pattern of the lungs, the TB bacilli usually lodge in the middle or lower lobes of the lung, although any lobe can become potentially infected.3877  Any bacillus that is not destroyed multiplies within the alveolar macrophages, is amplified within the cell, and then is released when the macrophage dies. Many of the bacilli are then ingested by, and grow within, monocytes or macrophages that have migrated from the bloodstream and accumulate at the site to form a microscopic lesion. A caseous center develops within the lesion, usually coinciding with increased antigenic load, at which time the host is likely tuberculin positive. At this stage the caseous lesion may heal or become a larger, stable lesion that can shed bacilli into the blood and lymph or liquefy and form a cavity (from which the bacilli enter the bronchial tree). Bacilli in liquefied caseum will grow extracellularly and spread to other parts of the lung and to the environment.3877 

Figure 887 – Transmission and Pathogenesis

VIEW LARGER IMAGE

Centers for Disease Control and Prevention (CDC). Transmission and Pathogenesis. CDC website. http://www.cdc.gov/tb/pubs/slidesets/core/Chapter2/trans1.htm Accessed July 11, 2009.

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During this period of logarithmic growth, the bacilli spread via lymphatic channels to the hilar and mediastinal lymph nodes and into the bloodstream to various locations in the body.3877  This seeding of different sites in the body sets up foci that may reactivate in the future if conditions are suitable (e.g., immunosuppression).

Two to 10 weeks after the initial infection, cell-mediated and delayed-type hypersensitivity immune responses begin to halt the rapid growth and dissemination of the TB bacilli. However, this does not usually lead to clearance of all the TB bacilli, and foci of viable TB bacilli remain dormant for years or decades until they may reactivate under permissible conditions. Approximately 95% of normal hosts develop acquired resistance containing the initial infection, and the TB becomes latent (latent TB); 5% of this group will eventually reactivate extrapulmonary or pulmonary foci. The remaining 5% of individuals will develop active TB following the initial infection.3861  The likelihood of reactivation is much higher in immunosuppressed individuals, including individuals treated with anti-tumor necrosis factor-α (anti-TNF-α) agents.3965,  6090 

Immunology of Tuberculosis and Tuberculosis in Immunocompromised Host

Mononuclear cells (macrophages and lymphocytic cellular infiltrate) are the major components of tuberculous lesions. Non-activated monocytes/macrophages allow tubercle bacilli to multiply within them. Upon activation, macrophages secrete a variety of substances that help kill and contain TB bacilli including elastase, collagenase, plasminogen activator, lysozyme, clotting factors, interferons, colony-stimulating factors, and a variety of cytokines. Cytokines play a major role in the formation of the tuberculous granuloma and also other key roles in TB containment by attracting lymphocytes and macrophages to the site, activating them, and stimulating them to proliferate. Activated macrophages are rich in enzymes that are effective in destroying ingested bacilli. T lymphocytes appear to have 2 main functions in the control of TB: killing poorly activated macrophages in which bacilli are multiplying and producing cytokines that activate macrophages.3862 

Acquired cellular immunity plays a major role in the body’s response to TB infection. It is characterized by a localized population of microbicidal macrophages activated by the cytokines of T lymphocytes. Populations of long-lived recirculating (memory) T lymphocytes with antigen-specific receptors keep the TB infection in check. Bacillary antigens secreted from TB-laden non-activated macrophages stimulate these memory T cells to release interleukin 2 (IL-2), which activates and increases proliferation of the specific T cells. The IL-2 also stimulates the release of interferon γ, which activates macrophages. The rapid accumulation and activation of local macrophages at the site of potential reactivation usually prevent the progression of new lesions. Delayed-type hypersensitivity plays a major role in the accumulation of lymphocytes and macrophages at the sites where the bacilli are lodged. However, if there is too much local antigen, delayed-type hypersensitivity causes tissue necrosis.3863 

TNF-α appears to play an important role in TB pathogenesis. Excessive TNF-α production and/or increased sensitivity to TNF-α are involved in the expression of many of the local and systemic toxicities evident with M. tuberculosis infections. TNF-α is an important mediator of systemic inflammation in this disease, clinically manifested by fever and wasting symptoms. TNF-α may also play a role in granuloma formation and containment of TB infection. Impairment of TNF-α secretion due to defective signaling through the interferon-γ receptor gene may be involved in disease progression. Depending on the setting, TNF-α either promotes containment or dissemination of M. tuberculosis and can contribute to either immune protection or pathology. Active TB is often the result of reactivation of a latent focus in immunocompromised patients.3877  TB is usually more severe and rapidly progressive in immunocompromised patients. Extrapulmonary involvement is more frequent. As a result, mortality is higher in these patients.

Epidemiology of Tuberculosis

In 2005, there were 14,097 newly reported cases of active TB in the US, an incidence of 4.8 cases per 100,000. There are 12 states and the District of Columbia that have reported rates higher than the national average of 4.8 cases per 100,000. Alaska, California, Florida, Georgia, Hawaii, Louisiana, Maryland, New Jersey, New York, South Carolina, Tennessee, and Texas accounted for 65% of the total national cases in 2005. Several of these states have large populations of immigrants who come from countries with high rates of TB. There is a higher incidence in non-white populations, particularly those of Asian background, and from countries with a high prevalence of TB.

Figure 881 – TB Case Rates, United States 2007


Centers for Disease Control and Prevention (CDC). TB case rates, United States 2007. http://www.cdc.gov/tb/pubs/slidesets/surv/surv2007/slides/surv4.htm. Accessed August 17, 2009.

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Figure 882 – Reported Tuberculosis Cases by Race/Ethnicity United States, 2007


Centers for Disease Control and Prevention (CDC). Reported tuberculosis cases by race/ethnicity, United States, 2007. CDC Web site. http://www.cdc.gov/tb/pubs/slidesets/surv/surv2007/slides/surv9.htm. Accessed August 17, 2009.

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In 2005, 55% of TB cases occurred in individuals born outside of the United States. The top 7 countries of origin of foreign-born persons with TB were Mexico, the Philippines, Vietnam, India, China, Haiti, and Guatemala.

Figure 883 – Number of TB Cases in U.S.-Born vs. Foreign-Born Persons U.S. 1993-2007


Centers for Disease Control and Prevention (CDC). Number of TB Cases in U.S.-Born vs. Foreign-Born Persons, United States 1993-2007. CDC website. http://www.cdc.gov/tb/pubs/slidesets/surv/surv2007/slides/surv11.htm. Accessed August 17, 2009.

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Figure 884 – Countries of Birth of Foreign-born Persons Reported With Tuberculosis, 2007


Centers for Disease Control and Prevention (CDC). Countries of birth of foreign-born persons reported with tuberculosis, 2007. http://www.cdc.gov/tb/pubs/slidesets/surv/surv2007/Slides/surv17.htm. Accessed August 17, 2009.

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Since 1993, when the CDC case report was expanded to include drug-susceptibility results, the proportion of patients in the US with primary multidrug-resistant TB, defined as resistance to at least isoniazid and rifampin, has decreased from 2.5% to approximately 1% in 1997 and has remained at this level through 2005.

Figure 885 – Primary Multidrug-Resistant Tuberculosis United States, 1993-2007


Centers for Disease Control and Prevention (CDC). Primary MDR TB United States, 1993-2007. CDC website. http://www.cdc.gov/tb/pubs/slidesets/surv/surv2007/Slides/surv20.htm. Accessed August 17, 2009.

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In 1993, the World Health Organization described TB as a global health issue and, in fact, called it an emergency.3872 

Risk Factors for Tuberculosis

Testing for TB is based on considerations of sensitivity, specificity, prevalence of TB in different groups, and risk for developing active infection. Therefore, the CDC has recommended 3 end points for defining a positive tuberculin reaction: ≥5 mm, ≥10 mm, and ≥15 mm of induration.3873,  3874 

Persons in the highest risk categories for development of active TB following initial infection with Mycobacterium tuberculosis are defined as having a positive reaction if they have ≥5 mm of induration. These persons include the following:

  • Human immunodeficiency virus (HIV)-positive persons

  • Individuals who have had recent contact with TB patients

  • Fibrotic changes on chest radiograph consistent with prior TB (untreated)

  • Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of ≥15 mg/day of prednisone for 1 month or more)3873 

  • Patients receiving or planning to receive anti-tumor necrosis factor-α agents3874,  3956 

Persons at intermediate risk for development of active TB following initial infection with M. tuberculosisare defined as having a positive reaction when ≥10 mm of induration is present, and include the following individuals:

  • Recent (within the last 5 years) immigrants from high prevalence countries, such as areas of Eastern Europe, Latin America, Asia, and Africa

  • Injection-drug users who are HIV negative or have an unknown HIV status

  • Residents and employees of high-risk congregate settings, such as:

    • Hospitals and other health care facilities

    • Prisons and jails

    • Long-term health care facilities for the elderly (i.e., nursing homes)

    • Residential facilities for patients with AIDS

    • Homeless shelters

  • Mycobacterial laboratory personnel

  • Persons with clinical conditions that place them at high risk for active disease, such as:

    • Diabetes mellitus

    • Silicosis

    • Chronic renal failure

    • Hematologic disorders such as leukemias and lymphomas

    • Other specific malignancies (such as carcinoma of the head or neck and lung)

    • Weight loss of >10% of ideal body weight

    • Gastrectomy

    • Jejunoileal bypass

  • Children younger than 4 years of age

  • Infants, children, and adolescents exposed to adults at high risk for active TB

Finally, persons at low risk (i.e., those with no risk factors) for development of TB following initial infection with M. tuberculosis are considered to have a positive reaction if ≥15 mm of induration is present.

Content on this page was last reviewed on March 11, 2009.

Content on this page was last changed on March 25, 2009.

References:

3859.  History of TB—an interesting timeline. Indian Chest Society website. http://www.indianchestsociety.org/about/timelinetb.html . Accessed March 3, 2007.
3861.  Ellner JJ. Review: the immune response in human tuberculosis — implications for tuberculosis control. J Infect Dis. 1997;176(5):1351-1359.
3862.  Giacomini E, Iona E, Ferroni L, et al. Infection of human macrophages and dendritic cells with Mycobacterium tuberculosis induces a differential cytokine gene expression that modulates T cell response. J Immunol. 2001;166(12):7033-7041.
3863.  Kaplan G, Freedman VH. The role of cytokines in the immune response to tuberculosis. Res Immunol. 1996;147(8-9):565-572.
3864.  Centers for Disease Control and Prevention (CDC). TB slide set surveillance 2005. CDC Web site. http://www.cdc.gov/nchstp/tb/pubs/slidesets/surv/surv2005/ . Accessed June 30, 2009.
3872.  World Health Organization (WHO). Global atlas and interactive mapping. WHO website. http://www.who.int/globalatlas/interactiveMapping/MainFrame2.asp . Accessed June 30, 2009.
3873.  American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161(4, pt 2):S221-S247.
3874.  Centers for Disease Control and Prevention. Tuberculosis associated with blocking agents against tumor necrosis factor-alpha—California, 2002-2003. MMWR Morb Mortal Wkly Rep. 2004;53(30):683-686.
3875.  Centers for Disease Control and Prevention (CDC). Transmission and pathogenesis. CDC website. http://www.cdc.gov/tb/pubs/slidesets/core/Chapter2/trans1.htm . Accessed July 11, 2009.
3877.  Leung AN. Pulmonary tuberculosis: the essentials. Radiology. 1999;210(2):307-322.
3907.  Watts HG, Lifeso RM. Tuberculosis of bones and joints. J Bone Joint Surg Am. 1996;78(2):288-298.
3956.  Tuberculin skin testing. Centers for Disease Control and Prevention website. http://www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250140.htm . Updated April 2006. Accessed June 30, 2009.
3965.  Centers for Disease Control and Prevention (CDC). Treatment options for latent tuberculosis infection. CDC website. http://www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250110.htm . Updated April 2006. Accessed June 30, 2009.
6090.  Centers for Disease Control and Prevention (CDC). Tuberculosis associated with blocking agents against tumor necrosis factor-alpha — California, 2002-2003. MMWR Morb Mortal Wkly Rep . 2004;53(30):683-686.
12037.  Centers for Disease Control and Prevention (CDC). Primary MDR TB United States, 1993-2007. CDC website. http://www.cdc.gov/tb/pubs/slidesets/surv/surv2007/Slides/surv20.htm . Accessed August 17, 2009.
12038.  Centers for Disease Control and Prevention (CDC). Reported tuberculosis cases by race/ethnicity, United States, 2007. CDC Web site. http://www.cdc.gov/tb/pubs/slidesets/surv/surv2007/slides/surv9.htm . Accessed August 17, 2009
12039.  Centers for Disease Control and Prevention (CDC). Number of TB cases in U.S.-born vs. foreign-born persons, United States 1993-2007. CDC website. http://www.cdc.gov/tb/pubs/slidesets/surv/surv2007/slides/surv11.htm . Accessed August 17, 2009.
12040.  Centers for Disease Control and Prevention (CDC). Countries of birth of foreign-born persons reported with tuberculosis, 2007. CDC website. http://www.cdc.gov/tb/pubs/slidesets/surv/surv2007/Slides/surv17.htm . Accessed August 17, 2009.
12041.  Centers for Disease Control and Prevention (CDC). TB cases rates, United States 2007. CDC Web site. http://www.cdc.gov/tb/pubs/slidesets/surv/surv2007/slides/surv4.htm . Accessed August 17, 2009.

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