Definition
Pulmonary tuberculosis is an infection (inflammation) caused by mycobacterium tuberculosis.

General Introduction

Human tuberculosis is caused by M. tuberculosis and M.bovis. Both organisms share one unique characteristics (acid fastness), but only the former can be cultured on artificial media.

Mycobacteria are uniquely capable of surviving within macrophages, and macrophages have to be activated in order to kill the intracellularly residing tubercle bacilli.

Tuberculosis and other mycobacterial infections (excluding leprosy) are becoming increasingly prevalent among compromised hosts, especially AIDS patients.

In man, the lungs are most commonly affected, but lesions may occur also in the kidneys, bones, lymph nodes, and meninges or be disseminated throughout the body.

Characteristics of the Etiological Agents

The route of infection (respiratory versus intestinal) determines the pattern of lesions.

In developed countries, M. bovis has become very rare.

Some "atypical" mycobacteria (e.g., Mycobacterium fortuitum) cause (see nontuberculous mycobacterial infections in compromised hosts).

• Immunological Characteristics

Microbiological Characteristics

Obligate Aerobic

• Why the lung is preferentially affected.
• Why the secondary infections start at the apex of the lung.

Acid-Fastness (For Mycobacteria, Gram Positiveness is Only Academic)

• Acid fast bacteria have the ability to retain dyes (fuchsin) when treated with acid solution (Ziehl-Neelsen stain).
• Useful for the detection of M. tuberculosis in clinical specimens (sputa, pus or tissues) by microscopy.

Special Nutritional Requirement (Lowenstein-Jensen Medium)

• TB cultures are not routinely done! Need special culture media.

Slow Grower

• Requires several weeks to form visible colonies! (DON'T CALL CLINICAL LABS FOR THE RESULT OF CULTURE NEXT DAY!)

Highly Resistent to Desiccation

• This is why most infections (TB) are initially caused by inhalation of contaminated dusts!

Facultative Intracellular Pathogen

• Neutrophils or resident macrophages can not kill this organism. M. tuberculosis prevents the acidification of phagolysomes, thus resists the intracellular microbicidal mechanisms of phagocytes.

Unique Cellular Constituents (Lipids)

• Stimulate cell-mediated immune response (delayed type hypersensitivity) of the host (see the pathogenic mechanisms and tuberculin test below).
• þ The constituents listed below are found largely in cell walls. Mycobacterial cell walls can induce delayed hypersensitivity, and replace whole mycobacterial cells in Freund's adjuvant.

Pathogenesis of Tuberculosis

Inhalation: Contaminated Dusts or Droplets

• This is the most common route of transmission of tuberculosis from person to person. Uniquely high resistance of M. tuberculosis to drying is responsible for this. M. tuberculosis within sputa can survive very long even after they are dried and air-borne. This is why tuberculosis is often acquired in over-crowded housing, jail cells, and other climatic conditions that exacerbated exposure. Physicians and other health care personnel are constantly at risk of infection.
• Most infections can be prevented or at least minimized by proper use of mask, sanitary care of rooms, and installation of good ventilation system.

Ingestion: Contaminated Milk (Uncommon in the Western World) - Tuberculosis Due to M. Bovis.

• Milk is routinely pasteurized to kill pathogens (that include tubercle bacilli).

Spread, Multiplication and Damage

Tubercle bacilli do not produce exotoxins or endotoxin. The severe manifestations of tuberculosis are linked to host reactions to the organisms; damage is caused by uncontrolled, progressive, chronic inflammation, and by organisms living with macrophages. It follows that infection has different manifestations in a "virgin" host than in a person who has been infected previously. Tuberculosis manifests itself in two major forms:

• Primary Tuberculosis
• Secondary or Reactivated Tuberculosis

Cellular Components of M. Tuberculosis Contributing to the Pathogenesis

Lipids
Mycobacteria are rich in lipids. Phosphatide fractions can produce tubercle like cellular responses and caseation necrosis. Lipids are to some extent responsible for acid-fastness. Virulent strains of tubercle bacilli form microscopic "serpentine cords" in which acid-fast bacilli are arranged in parallel chains. Cord formation is correlated with virulence. A "cord factor" (trehalose-6,6'-dimycolate) has been extracted from virulent bacilli with petroleum ether. It inhibits migration of leukocytes, causes chronic granulomas, and can serve as an immunologic "adjuvant".

Proteins
Each type of mycobacterium contains several proteins that elicit the tuberculin reaction. Proteins bound to a wax fraction can, upon injection, induce tuberculin sensitivity. They can also elicit the formation of a variety of antibodies.

Polysaccharides
Mycobacteria contain a variety of polysaccharides. They can induce the immediate type of hypersensitivity (clinically not relevant).

Heat Shock Proteins

Pathology

The characteristic pathologic changes depend on the type of infection or "exposure." If the primary lesion could not contained rapidly, the appearance of hypersensitivity to tuberculin (see below) provokes a dramatic change in the host's response to the organisms. The nonspecific inflammatory response evoked on first exposure to tubercle bacilli becomes granulomatous, evoking the formation of tubercles. The tubercle comprises an organized aggregation of enlarged macrophages that, because they resemble epithelial cells, are referred to as epithelioid cells. A peripheral collar of fibroblasts, macrophages, and lymphocytes surrounds the granuloma. Frequently the central region of epithelioid cells undergoes a characteristic caseous necrosis to produce a "soft" tubercle, the most characteristic hallmark of tuberculosis. When the antigen load at the initial infection site and regional lymph node is large, caseation necrosis may develop and lesions may later calcify.

• Primary pulmonary TB (primary exposure) is characterized by the Ghon complex and consists of 1.) subpleural (fissure) focus of inflammation. 2.) Infected (inflamed) lymph nodes draining the primary, subpleural lesion.
• Secondary pulmonary TB (reactivation) is characterized by a focus of infection and granuloma formation usually in the apex of the lung. The small granulomas (tubercles) eventually coalesce to form larger areas of consolidation with central caseating necrosis. Regional lymph nodes contain caseating granulomas.   Secondary TB has a much high incidence of large areas of caseating necrosis. Otherwise, primary and secondary TB are histologically similar
• Progressive pulmonary TB: Primary or secondary TB may go on to heal .Caseating granulomas are replaced by fibrosis and calcification. However, cases that do not heal spontaneously or with therapy  progress to form cavities or spread to other parts of the lung and other organs of the body through lymphatic channels and the blood stream. This type of spread is known as miliary tuberculosis.
• The histologic hallmark is caseating granulomata with Langhan's-type giant cells. The granuloma is a rounded collection of macrophages and lymphocytes containing multinucleated giant cells, the nuclei of which are arranged at the periphery in a horse-shoe shape
• Acid-fast bacilli can sometimes be demonstrated by the Zeihl-Neelson stain on tissue sections. Cultures are much more sensitive. The organisms are abundant in immmunocompromised host as in HIV patients.

Primary Tuberculosis

When the host encounters with M. tuberculosis for the first time, the following events occur:

• Settlement in alveoli.
• Local inflammatory response -Encounter with neutrophils and resident macrophages.
• Transport of engulfed bacilli (resident macrophages or neutrophils can not kill tubercle bacilli) to regional lymph nodes. They continue to multiply intracellularly.
• Killing of the phagocytosed tubercle bacilli occurs only when macrophages are activated. (Recall Immunology lectures - how cellular responses to certain bacteria and lymphokines activate macrophages). Simultaneously, the development of cell-mediated immunity, and delayed type hypersensitivity to tuberculin (antigenic protein(s) produced by M. tuberculosis.
• If the host defense system fails to contain the spread of the bacilli at this point, the following events ensue. It is estimated that approximately 10% of individuals with normal immunity well develop active TB within their lifetime, 5% within the first 2 years of infection.
• Caseation of lymph nodes.
• Spread of organisms within the host: Tubercle bacilli spread in the host by direct extension, through the lymphatic channels and bloodstream, and via the bronchi and gastrointestinal tract. These events result in tuberculous meningitis, miliary tuberculosis or both.
• If a caseating lesion discharges its contents into a bronchus, they are aspirated and distributed to other parts of the lungs or are swallowed and passed into the stomach and intestines.

As illustrated above, when a host has first contact with tubercle bacilli:

1. An acute exudative lesion develops and rapidly spreads to the lymphatics and regional lymph nodes. The exudative lesion in tissue often heals rapidly.
2. The lymph node undergoes caseation, which usually calcifies.
3. The tuberculin test becomes positive.

Progressive primary infection:

After the development of hypersensitivity, the infection becomes quiescent and asymptomatic in the majority of patients (about 90%). In some, however, especially the very young and adults who are immunocompromised or who have other predisposing illnesses, the primary infection may evolve into clinical disease. The progression may be local at the site of the primary lesion, or it may be at one or more distant sites where bacilli have arrived during the early hematogenous spread.

Secondary or Reactivated Tuberculosis

In a small number of persons whose initial tuberculous infection subsidies, secondary disease occurs in spite of acquired cellular immunity.

Secondary tuberculosis is usually due to the reactivation of old lesions.

The characteristics of secondary tuberculosis include extensive tissue damages due to immunologic reactions of the host to tubercle bacilli and their products.

In this phase of the disease, lesions are usually localized in the apices of the lungs (remember that tubercle bacilli require oxygen for growth).

In about 5% of patients, apical pulmonary tuberculosis manifests itself within 2 years of the primary infection. In others, however, clinical disease may evolve many decades later whenever resistance is lowered.

Quiescent foci that harbor viable organisms thus remain a potential hazard throughout a person's lifetime.

Because of the acquired cellular immunity, bacilli are more promptly phagocytized and destroyed by the activated macrophages. As a result, in secondary tuberculosis, lesions remain localized and dissemination of organisms via the lymphatic vessels is usually prevented.

Hypersensitivity promotes a more rapid caseation and fibrotic walling-off of the focus. Histologically the reaction is characteristic of tubercle formation, manifested by a local accumulation of lymphocytes and macrophages.

T lymphocytes and their chemotactic lymphokines play a major role in the development of tuberculous granuloma.

These differences between primary infection and post-primary or reactivation are attributed to (1) resistance and (2) hypersensitivity induced by the first infection of the host with tubercle bacilli.

Therapy:

References: Sherris Medical Microbiology, Chapter 27 

Last Updated: January 13, 2000   Created: March 14, 1996