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Infectious Disease Online

Pathology of Tuberculosis

Dr Sampurna Roy MD




Tuberculosis is a chronic communicable disease caused by a variety of tubercle bacilli (Mycobacterium tuberculosis hominis and Mycobacterium tuberculosis bovis) and has over centuries been responsible for disease and death in all social strata.


The lungs are the prime target, but any organ may be infected.


The characteristic lesion is a spherical granuloma with central caseous necrosis.

(i) Mycobacterium tuberculosis hominis is ordinarily contracted by inhaling contaminating droplets.

(ii) Mycobacterium tuberculosis bovis is contracted through the gastrointestinal tract, from the raw milk of diseased cows.

Most people, after exposure, develop a small, limited pulmonary infection.

This infection is contained by an inflammatory reaction, and during this course the tuberculin skin test becomes positive.

Thus most tuberculous infections do not progress to clinical disease.

Distributed throughout the world, tuberculosis is clearly one of the most important bacterial diseases of mankind.

Tubercle bacilli are slender, beaded non-motile, acid-fast, and gram-positive bacilli, although their gram-positivity may be difficult to demonstrate.

The cell wall is waxy and contains components that confer acid-fastness ; that is, the retention of carbol fuchsin after rinsing with acid alcohol.

Tubercle bacilli are strict, obligate aerobes that proliferate within phagocytes.

They grow slowly in culture and require 3 or more weeks to develop colonies.

The virulence of tubercle bacilli is associated with a tendency to aggregate and form filaments or cords in liquid media.

The organisms resist heat and disinfectants but are killed quickly by ultraviolet light.

Delayed cell mediated immunity to tubercle bacillus is commonly measured by the Mantoux skin test, which use as test antigen the “purified protein derivative” from media in which tubercle bacilli have grown.

The skin test is positive if an area of induration at least 10 mm in diameter develops within 48 hours after the intradermal injection of the antigen.

Patients usually develop this hypersensitivity 2 to 4 weeks after infection.

Although a positive skin test indicates infection with tubercle bacilli, it is not necessarily associated with clinical disease.

Most people with positive skin tests have immune systems that have confined and limited the infection.

A positive skin test also develops after vaccination with Bacilli Calmette-Guerin (BCG). When BCG is used in an effort to control natural tuberculosis, the skin test is not reliable as an indicator of naturally acquired infection. Once positive, the person remains so for life.

Before the patient develops sensitivity, bacilli multiply unchecked and may move through lymphatics and blood stream to distant sites.

The cellular basis of the positive test is granulomatous response, composed of epithelioid cells and giant cells.

At first, when there is uncontrolled growth of bacilli, the reaction is histiocytic and necrotizing.

But with time, the appearance of epithelioid cells signals the destruction of bacilli and the limitation of the infection.

Hypersensitivity (resistance to infection) is associated with increased phagocytosis of bacilli, conversion of macrophages to epithelioid cells, the formation of giant cells, and the inhibition of intracellular replication of tubercle bacilli.


Visit: Cutaneous Tuberculosis - Lupus Vulgaris


Primary Tuberculosis:

Primary Tuberculosis is an infection of persons who have not had prior contact with the tubercle bacillus.


The bacilli usually enter the body by inhalation but can also enter through the gastrointestinal tract or by cutaneous or subcutaneous inoculation.


Inhaled bacilli are commonly deposited in alveoli immediately beneath the pleura, usually in the lower part of the upper lobes or the upper part of the lower lobes.


These areas receive the greatest volume of inspired air.


The initial infection produces only slight abnormalities and may cause only slight malaise and mild fever.


Since sensitized T cells are lacking, the tubercle bacilli multiply freely and enter the blood stream and lymphatics.


Cell-mediated immunity develops over a period of 3 to 6 weeks.

The primary infection characteristically produces a “Ghon complex”- that is, a single lesion in the pulmonary parenchyma, usually subpleural, that is accompanied by a lesion of the hilar lymph nodes draining that part of the lung.

The primary lesion, or Ghon focus, in the lung is typically a 1cm, grayish, circumscribed nodule.

It becomes granulomatous within a few days and by the second week has soft caseous, necrotic center.

Tubercle bacilli drain through lymphatic channels to infect the hilar lymph nodes and form the second part of the Ghon complex.

In over 90% of normal adults the infection follows this self-limited course, because the cellular immune response is sufficient to control the multiplication of bacilli.

Therefore, in both the lung and the lymph nodes the lesions of the Ghon complex heal, undergoing shrinkage, fibrous scarring, and calcification.

Most of the organisms die, but a few remain viable for years.

Later, if immune mechanisms wane or fail, the resting bacilli may break out and cause serious tuberculous infection.

Progressive primary tuberculosis is a rarer alternative  course, in which the immune response fails to control multiplication of the tubercle bacilli.

Infection takes this course in less than 10% of normal adults, but it is common in children under 5 years of age.

In adults, progressive primary tuberculosis most commonly occurs in patients with suppressed or defective immunity.

The primary Ghon focus in the lung enlarges rapidly, erodes the bronchial tree, and spreads, a sequence that results in adjacent “satellite” lesions.

This process is accompanied by caseous enlargement of the hilar lymph nodes, which may erode through the wall of the bronchus and discharge bacilli, thereby producing tuberculous pneumonia.

Clinical manifestations are abrupt high fever (associated with progression to tuberculous pneumonia), pleurisy with effusion, and lymphadenitis.

The highly active lesions may seed the blood stream with tubercle bacilli and result in life-threatening dissemination of the bacilli.



Secondary Tuberculosis:

Secondary (cavitary) tuberculosis usually results from reactivation of dormant, endogenous tubercle bacilli in a sensitized patient who has had previous contact with the tubercle bacillus.

In some cases, the disease is caused by reinfection with exogenous bacilli.

Secondary tuberculosis may develop any time after primary infection, even decades later.

Reactivation typically begins in the apical or posterior segments of one or both upper lobes (Simon’s foci), where the organisms were seeded during the primary infection.

Radiographically, the lesions are spherical and cavitary- the so-called coin lesions. A fibrous capsule surrounds the caseous, acellular center, which contains numerous tubercle bacilli.

From these cavitary nodules the organisms can spread through the lung and be discharged into the air during bouts of coughing.

The symptoms of secondary tuberculosis begin with cough, which may be erroneously attributed to smoking or to a “cold”.

Low-grade fever develops, with general malaise, fatigue, anorexia, weight loss, and often night sweats.

As the disease progresses, the cough worsens and the sputum may be streaked with blood. The rupture of a branch of the pulmonary artery in the wall of a cavity leads to massive hemoptysis and asphyxiation or exanguination.

These pulmonary lesions of secondary tuberculosis are often complicated by a variety of secondary effects, including :

(1) Scarring and calcification;

(2) Spread to other areas;

(3) Pleural fibrosis and adhesions, with associated pleurisy, sharp  pleuritic pain, and shortness of breath;

(4) Rupture of a caseous lesion, which spills bacilli into the pleural cavity;

(5) Erosion into a bronchus, which seeds the mucosal lining of bronchioles, bronchi, and trachea; and

(6) Implantation of bacilli in the larynx, which causes laryngitis, hoarseness, and pain on swallowing.

Lesions of secondary tuberculosis acquired through the gastrointestinal tract (usually with M. t. bovis) can lead to entrapment of bacilli in lymphoid patches of small and large bowel.


Miliary Tuberculosis:

Miliary tuberculosis is the disseminated form of tuberculosis and is caused by seeding of the bacilli through lymphatics or blood vessels to produce minute, yellow-white lesions resembling millet seeds (hence military).

The lung, lymph nodes, kidneys, adrenals, bone marrow, spleen, liver, meninges, brain, eye grounds, and genitalia are common sites of miliary lesions.

Miliary tubercles rarely develop in the pancreas, thyroid, striated muscle, or heart.

Regardless of the organs involved, all granulomas have similar features and follow the same progression, namely focal collections of histiocytes, followed by epithelioid cells, Langhan’s giant cells, central caseation necrosis and eventually fibrosis and mineralization.

Diagnosis of Tuberculosis:

Clinical suspicions of tuberculosis are confirmed by the microscopic demonstration of acid-fast bacilli within smears of sputum.

The diagnosis is usually confirmed by the demonstration, within tissue sections from effected organs, of bacilli that have a symmetric or consistent relationship to the lesions.

The slender, rod shaped and slightly curved orgnanisms are acid-fast stain  intensely red with carbol-fuchsin and are found in the granuloma.

Bacilli are usually found in the caseous centers or in histiocytes or giant cells at the perimeter.

The detection of acid fast bacilli in granulomas may be problematic and is largely dependent on the underlying response that is initiated by the patient's immune system.

In those patients in whom there is a vigorous granulomatous reaction, few if any bacilli are found and microbiological confirmation of the disease depends on culture or molecular identification of mycobacterial genomic material. Both Mycobacterium T. hominis and Mycobacterium T. bovis can be cultured from sputum or tissue specimens.  

M. tuberculosis bacilli are best identified in tissue sections using the Ziehl-Neelsen or Triff stains.

The latter stain is particularly good at demonstrating the organisms and the backround tissue allowing the histopathologist to better visualise and correlate the pathological process, specially important if scanty bacilli are present.

Silver impregnation methods such as the Dieterle or Warthin Starry are more sensitive and may be used to assist with the identification of mycobacteria in those cases where carbol-fuchsin methods have failed ; they show beaded bacilli, nocardia-like filamentous organisms and granular debris probably representing degenerate mycobacteria. Their specificity is limited as morphological similarities  are shared with cat scratch disease and nocardiosis.

Fluorescence microscopy using the Auramine-Rhodamine and Papanicolaou stains may also be used to identify bacilli in cytological specimens. An immunohistochemical method has also been developed.

Treatment of Tuberculosis:

Tuberculosis is effectively treated with at least two bactericidal or bacteriostatic drugs.

Companion drugs are included to provide activity against bacilli that are resistant to the primary drug.

To succeed, the chemo- therapeutic regimen must eliminate extracellular bacilli in both solid and cavitary lesions, and intracellular bacilli in histiocytes or in giant cells.

Among the drugs in use isoniazid, rifampin, streptomycin, capreomycin and kanamycin, pyrazinamide, ethambutol, para-aminosalicylic acid (PAS), ethionamide, and thiacetazone.

Isoniazid is the most valuable antituberculous drug, since it can be taken orally as well as parenterally and kills both extracellular and intracellular bacilli and is especially important for eradicating “persisters” during the continuation phase.


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Dr Sampurna Roy  MD

Consultant  Histopathologist (Kolkata - India)  ;  Dermpath-India  ;   Soft Tissue Tumour Online ; Cardiac Path Online ;

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