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General Features

Mycobacterium tuberculosis is the organism that is the causative agent for tuberculosis (TB). There are other "atypical" mycobacteria such as M. kansasii that may produced a similar clincal and pathologic appearance of disease. M. avium-intracellulare (MAI) seen in immunocompromised hosts (particularly in persons with AIDS) is not primarily a pulmonary infection in terms of its organ distribution (mostly in organs of the mononuclear phagocyte system).

Tuberculosis is becoming a world-wide problem. War, famine, homelessness, and a lack of medical care all contribute to the increasing incidence of tuberculosis among disadvantaged persons. Since TB is easily transmissible between persons, then the increase in TB in any segment of the population represents a threat to all segments of the population. This means that it is important to institute and maintain appropriate public health measures, including screening, vaccination (where deemed of value), and treatment. A laxity of public health measures will contribute to an increase in cases. Failure of adequate treatment promotes the development of resistant strains of tuberculosis.

Patterns of Infection

There are two major patterns of disease with TB:

• Primary tuberculosis: seen as an initial infection, usually in children. The initial focus of infection is a small subpleural granuloma accompanied by granulomatous hilar lymph node infection. Together, these make up the Ghon complex. In nearly all cases, these granulomas resolve and there is no further spread of the infection.
• Secondary tuberculosis: seen mostly in adults as a reactivation of previous infection (or reinfection), particularly when health status declines. The granulomatous inflammation is much more florid and widespread. Typically, the upper lung lobes are most affected, and cavitation can occur.

When resistance to infection is particularly poor, a "miliary" pattern of spread can occur in which there are a myriad of small millet seed (1-3 mm) sized granulomas, either in lung or in other organs.

Dissemination of tuberculosis outside of lungs can lead to the appearance of a number of uncommon findings with characteristic patterns:

Skeletal Tuberculosis: Tuberculous osteomyelitis involves mainly the thoracic and lumbar vertebrae (known as Pott's disease) followed by knee and hip. There is extensive necrosis and bony destruction with compressed fractures (with kyphosis) and extension to soft tissues, including psoas "cold" abscess.

Genital Tract Tuberculosis: Tuberculous salpingitis and endometritis result from dissemination of tuberculosis to the fallopian tube that leads to granulomatous salpingitis, which can drain into the endometrial cavity and cause a granulomatous endometritis with irregular menstrual bleeding and infertility. In the male, tuberculosis involves prostate and epididymis most often with non-tender induration and infertility.

Urinary Tract Tuberculosis: A "sterile pyuria" with WBC's present in urine but a negative routine bacterial culture may suggest the diagnosis of renal tuberculosis. Progressive destruction of renal parenchyma occurs if not treated. Drainage to the ureters can lead to inflammation with ureteral stricture.

CNS Tuberculosis: A meningeal pattern of spread can occur, and the cerebrospinal fluid typically shows a high protein, low glucose, and lymphocytosis. The base of the brain is often involved, so that various cranial nerve signs may be present. Rarely, a solitary granuloma, or "tuberculoma", may form and manifest with seizures.

Gastrointestinal Tuberculosis: This is uncommon today because routine pasteurization of milk has eliminated Mycobacterium bovis infections. However, M. tuberculosis organisms coughed up in sputum may be swallowed into the GI tract. The classic lesions are circumferential ulcerations with stricture of the small intestine. There is a predilection for ileocecal involvement because of the abundant lymphoid tissue and slower rate of passage of lumenal contents.

Adrenal Tuberculosis: Spread of tuberculosis to adrenals is usually bilateral, so that both adrenals are markedly enlarged. Destruction of cortex leads to Addison's disease.

Scrofula: Tuberculous lymphadenitis of the cervical nodes may produce a mass of firm, matted nodes just under the mandible. There can be chronic draining fistulous tracts to overlying skin. This complication may appear in children, and Mycobacterium scrofulaceum may be cultured.

Cardiac Tuberculosis: The pericardium is the usual site for tuberculous infection of heart. The result is a granulomatous pericarditis that can be hemorrhagic. If extensive and chronic, there can be fibrosis with calcification, leading to a constrictive pericarditis.

Microscopic Findings

Microscopically, the inflammation produced with TB infection is granulomatous, with epithelioid macrophages and Langhans giant cells along with lymphocytes, plasma cells, maybe a few PMN's, fibroblasts with collagen, and characteristic caseous necrosis in the center. The inflammatory response is mediated by a type IV hypersensitivity reaction. This can be utilized as a basis for diagnosis by a TB skin test. An acid fast stain (Ziehl-Neelsen or Kinyoun's acid fast stains) will show the organisms as slender red rods. An auramine stain of the organisms as viewed under fluorescence microscopy will be easier to screen and more organisms will be apparent. The most common specimen screened is sputum, but the histologic stains can also be performed on tissues or other body fluids. Culture of sputum or tissues or other body fluids can be done to determine drug sensitivities.

1. Granulomas in lung, low power microscopic.
2. Granuloma with caseous necrosis, high power microscopic.
3. Granuloma with epithelioid macrophages and a Langhans giant cell, high power microscopic.
4. Granulomatous endometritis, high power microscopic.
5. Ziehl-Neelsen acid fast stain, microscopic, AFB stain.
6. Auramine stain, M. tuberculosis, fluorescence microscopy.

Tuberculin Skin Testing

Skin testing for tuberculosis is useful in countries where the incidence of tuberculosis is low, and the health care system works well to detect and treat new cases. In countries where BCG vaccination has been widely used, the TB skin test is not useful, because persons vaccinated with BCG will have a positive skin test.

The TB skin test is based upon the type 4 hypersensitivity reaction. If a previous TB infection has occurred, then there are sensitized lymphocytes that can react to another encounter with antigens from TB organisms. For the TB skin test, a measured amount (the intermediate strength of 5 tuberculin units, used in North America) of tuberculin purified protein derivative (PPD) is injected intracutaneously to form a small wheal, typically on the forearm. In 48 to 72 hours, a positive reaction is marked by an area of red induration that can be measured by gentle palpation (redness from itching and scratching doesn't count). Reactions over 10 mm in size are considered positive in non-immunocompromised persons.

Repeated testing may increase the size of the reaction (induration), but repeated TB skin testing will not lead to a positive test in a person not infected by TB. Anergy, or absence of PPD reactivity in persons infected with TB, can occur in immunocompromised persons, or it may even occur in persons newly infected with TB, or in persons with miliary TB.

1. Injecting PPD intracutaneously, gross.
2. A properly placed TB skin test, gross.
3. A positive TB skin test, gross.

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