Tuberculosis Granuloma Notes

Common Examples Of Granulomatous Inflammation

Granulomatous inflammation is typical of a reaction to poorly digestible agents.

These agents may be infectious or non-infectious:

• Infectious causes:  These are mycobacteria (for example, Tuberculosis, leprosy), bacteria (for example, Actinomycosis), spirochetes (for example, Syphilis), fungi infections (for example, Cryptococcosis), parasites (for example schistosomiasis).
• Noninfectious causes:  These include exogenous agents (for example, Foreign particles, berylliosis etc), and immune causes (for example, Crohn’s disease).

Read And Learn More Infammation And Repair Pathology 

A list of important and common examples of granulomatous conditions, their etiologic agents and salient features is given in Table.

• Tuberculosis: Tissue response to causative agent, Mycobacterium tuberculosis, represents a classical example of chronic granulomatous inflammation in humans.
• Incidence: In spite of great advances in chemotherapy and immunology, tuberculosis still continues to be a major public health problem in the entire world; roughly one-fourth of world’s population is infected with tuberculosis.
  • However, all patients infected with M. tuberculosis may not develop clinical disease since many cases remain reactive to tuberculin without developing symptomatic disease.
  • Out of estimated 10 million new cases annually, about 95% occur in developing countries of Asia, Africa and Latin America. In fact, India accounts for about a quarter of the global burden of tuberculosis (~3 million annually).
  • Factors contributing to a higher incidence of tuberculosis are malnutrition, inadequate medical care, poverty, crowding, chronic debilitating conditions such as uncontrolled diabetes, alcoholism and immunocompromised states.
  • In Western countries, there has been a resurgence of tuberculosis due to HIV-AIDS.
  • Observations in different populations suggest that besides these factors, genetic factors also play a key role which is responsible for varying degrees of susceptibility to tuberculosis in different individuals.

Principal granulomatous conditions:

Hiv-Associated Tuberculosis

HIV-infected individuals have a very high incidence of tuberculosis all over the world. Vice-versa, the rate of HIV infection in patients with tuberculosis is very high.

• Moreover, HIV-infected individual on acquire infection with tubercle bacilli develops active disease rapidly (within a few weeks) rather than after months or years.
• Although pulmonary tuberculosis in HIV presents in a typical manner, it is more often sputum smear-negative and often culture-positive.
• Besides, extrapulmonary tuberculosis is more common in HIV disease and manifests commonly by involving lymph nodes, pleura, pericardium, and tuberculous meningitis.
• Infection with M.aviumintracellulare (avian or bird strain) is more common in patients with HIV/AIDS. India is also the country with the second highest number of cases of HIV-associated tuberculosis, next only to South Africa.

Etiologic Agent:

Tubercle bacillus (TB) or Koch’s bacillus (named after the discovery of the organism by Robert Koch in 1882) or Mycobacterium tuberculosis causes tuberculosis in the lungs and other tissues of the human body.

• The organism is a strict aerobe and thrives best in tissues with high oxygen tension such as in the apex of the lung.
• Out of various pathogenic strains for human disease included in the Mycobacterium tuberculosis complex, the most common strain is M. tuberculosis hominins (human strain), while M.tuberculosis bovis (bovine strain) used to be a common pathogen to human beings during the era of consumption of unpasteurised milk but presently constitutes a small number of human cases.
• Other less common strains included in the complex are M.africanum (isolated from patients from parts of Africa), M.microti, M. pinnipedii and M.canettii. A non-pathogenic strain, M.smegmatis, is found in the smegma and may be seen as a contaminant in the urine of both men and women.

M. tuberculosis hominins is a slender rod-like bacillus, 0.5 µm by 3 µm, is neutral on Gram staining and can be demonstrated by the following methods:

•  Acid-fast (Ziehl-Neelsen) staining:  The acid-fastness of the tubercle bacilli is due to mycolic acids, cross-linked fatty acids and other lipids in the cell wall of the organism making it impermeable to the usual stains.
  • It takes up stain by heated carbol fuchsin and resists decolourisation by weak acids and alcohols (acid-fast and alcohol-fast) and can be decolourised by 20% sulphuric acid (compared to 5% sulphuric acid for decolourisation for M.leprae which are less acid fast).
  • However, false positive AFB staining may occur due to Nocardia, Rhodococcus, Legionella, and some protozoa such as Isospora and Cryptosporidium.
• Fluorescent method: The traditional method employs fluorescent dyes such as auramine and rhodamine for the presence of mycobacteria.
  • More recently, mycobacterial growth indicator tubes are used which have fluorescent compounds sensitive to the presence of oxygen dissolved in a liquid medium.
  • In this, the detection of mycobacterial growth is done by fluorometric technology as indicated by the appearance of fluorescence.
• Culture methods:   Mycobacteria from sputum or any other material can be cultured in Lowenstein-Jensen (LJ) medium by conventional method and has high specificity but the growth is slow and takes 4-8 weeks.
  • Currently, rapid methods (for example, Bactec culture, high-pressure liquid chromatography or HPLC of mycolic acids) are also available reducing the duration for bacteriologic confirmation to 2-3 weeks.
  • However, tissue specimens obtained for culture should not be put in formalin. The Guinea pig inoculation method by subcutaneous injection of the organisms is rarely used now.

• Molecular methods: These include nucleic acid amplification (for example, PCR) techniques which are most useful for species confirmation and for the distinction between M. tuberculosis and nontuberculous mycobacteria because the treatment between the two is quite different.
•  Immunohistochemical stain:  These are immunostains against mycobacterial antigens (for example, Anti-MTP64 antibody stain) which can be used in tissue sections to demonstrate the organism.
• Serologic tests:  Several serologic test kits for the detection of antibodies to a variety of mycobacterial antigens are commercially available in developing countries. However, they have low sensitivity, specificity and poor reproducibility.

Hence, they are not useful for diagnostic aids and WHO in 2011 issued a negative recommendation on their use for the diagnosis of tuberculosis.

Atypical Mycobacteria (Non-Tuberculous Mycobacteria)

The term atypical mycobacteria or non-tuberculous mycobacteria (NTM) is used for mycobacterial species other than M. tuberculosis complex and M. leprae.

• NTM are widely distributed in the environment and are, therefore, also called environmental mycobacteria.
• They too are acid-fast. NTM are non-pathogenic to guinea pigs but occasionally may cause human tuberculosis which is resistant to usual anti-tubercular drugs.

Conventionally, NTM is classified based on the colour of the colony produced in culture and the speed of growth in media:

• Rapid growers: These organisms grow fast on solid media (within 7 days) but are less pathogenic than others. Examples include M.abscessus, M. fortuitum, M.chelonae.
• Slow growers: These species grow mycobacteria on solid media (in 2-3 weeks).

Based on the colour of the colony formed, they are further divided into the following:

• Photochromogens These organisms produce yellow pigment in the culture grown in light.
• Scotochromogens Pigment is produced, whether the growth is in light or in dark.
• Non-chromogens No pigment is produced by the bacilli and the organism is closely related to avium bacillus.

Examples of slow growers are M. avium-intracellulare, M. kansasii, M. ulcerans and M. fortuitum.

• The infection by NTM is acquired directly from the environment, unlike the person-to-person transmission of classical tuberculosis.
• They produce human disease, atypical mycobacteriosis, similar to tuberculosis but are much less virulent.
• The lesions produced may be granulomas, nodular collection of foamy cells, or acute inflammation.

Five patterns of the disease are recognised:

1. Pulmonary disease produced by M.kansasii or M.avium-intracellular
2. Lymphadenitis caused by M.avium – intracellular or M. scrofulaceum
3. Ulcerated skin lesions produced by M.ulcerans or M. marinum
4. Abscesses caused by M.fortuitum or M. chelonae
5. Bacteraemias by M.avium-intracellular as seen in immunosuppressed patients of AIDS.

Mode Of Transmission

Human beings acquire infection with tubercle bacilli by one of the following routes:

1. Inhalation:  Inhalation of organisms present in fresh cough droplets or in dried sputum from an open
   case of pulmonary tuberculosis.
2. Ingestion: Ingestion of the organisms leads to the development of tonsillar or intestinal tuberculosis. This mode of infection of human tubercle bacilli is from self-swallowing of infected sputum of an open case of pulmonary tuberculosis, or ingestion of bovine tubercle bacilli from the milk of diseased cows.
3. Inoculation: Inoculation of the organisms into the skin may rarely occur from infected postmortem tissue.
4. Transplacental: Transplacental route is a rare mode of transmission and may cause congenital tuberculosis in the foetus from an infected mother.

Spread Of Tuberculosis

The disease spreads in the body by various routes:

• Local spread:  This takes place by macrophages carrying the bacilli into the surrounding
  tissues.
• Lymphatic spread:  Tuberculosis is primarily an infection of lymphoid tissues. The bacilli
  may pass into lymphoid follicles of the pharynx, bronchi, intestines or regional lymph nodes resulting in regional tuberculous lymphadenitis which is typical of childhood infections. The primary complex is the primary focus with lymphangitis and lymphadenitis.
• Haematogenous spread:  This occurs either as a result of tuberculous bacillaemia because of the drainage of lymphatics into the venous system or due to caseous material escaping through the ulcerated wall of a vein. This produces miliary tuberculosis characterised by millet seed-sized lesions in different organs of the body such as lungs, liver, kidneys, bones and other tissues.
• By the natural passages:  Infection may spread from:
  • Lung lesions into pleura (tuberculous pleurisy)
  • Transbronchial spread into the adjacent lung segments
  • Tuberculous salpingitis into the peritoneal cavity (tuberculous peritonitis)
  • Infected sputum into the larynx (tuberculous laryngitis)
  • Swallowing of infected sputum (ileocaecal tuberculosis), and
  • Renal lesions into the ureter and down to the trigone of the bladder.