Tuberculosis - I.T. Pyatnochka 2005

Etiopathogenesis and Pathological Anatomy of Tuberculosis

The tuberculosis pathogen belongs to a broad group of mycobacteria related to lower plant organisms—actinomycetes, or ray Fungi (derived from the Greek words actis, meaning ray, and myces, meaning fungus). Various terms are used to refer to the tuberculosis pathogen: Koch's bacilli, Koch's bacilli rods, and Mycobacterium tuberculosis.

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (MTB) belonging to the genus Mycobacterium, family Mycobacteriaceae, and order Actinomycetales.

The genus Mycobacterium within the family Mycobacteriaceae comprises acid- and alcohol-fast, aerobic, non-motile, Gram-positive straight or curved rod-shaped Bacteria. They grow slowly or very slowly (saprophytic species grow considerably faster). Mycobacteria are widely distributed in the environment—in Water, soil, plants, and animals. Approximately 50 species have currently been identified, while the genus encompasses about 200 species; the type species is Mycobacterium tuberculosis. Based on pathogenicity, they are divided into strictly pathogenic species, which cause specific diseases, and atypical mycobacteria, which include opportunistic pathogens and Saprophytes. Atypical mycobacteria (According to the Runyon Classification, 1959) are divided into 4 groups based on colony pigmentation and growth rate: Group I—photochromogens, which form pigment upon exposure to light (M. kansasii, M. marinum); Group II—scotochromogens, the most widespread group, which produce a yellow-orange pigment in the dark (M. aquae, M. flavescens, M. scrofulaceum, M. gordonae, and M. paraffinicum); Group III—non-photochromogens, which produce no pigment or only minimal amounts (M. xenopi, M. avium, M. intracellularae, M. gastri, M. nonchromogenicum, M. terrae, M. triviale); Group IV—rapidly growing species (M. phlei, M. smegmatis, M. fortuitum, M. marinum).

Depending on their pathogenicity for humans and various animals, pathogenic mycobacteria include the following species:

M. tuberculosis (human strain)—the CAUSATIVE AGENT OF human tuberculosis;

M. bovis (bovine strain)—the causative agent of bovine tuberculosis;

M. africanum (African strain)—isolated in tropical West Africa, possessing characteristics of both preceding species.

M. tuberculosis consists of slender or slightly Curved Rods measuring 1.0–10.0 × 0.2–0.6 µm with slightly rounded ends. Their Cytoplasm contains granular formations (2–10); they do not form spores and lack capsules (Figs. 4, 5). They are Gram-positive aerobes. A crucial feature is their acid-, alkali-, and alcohol-fastness, which is attributed to the presence of a lipid fraction, specifically mycolic acid. They multiply slowly by simple binary fission, on average every 14–18 hours. Occasionally, MTB multiply by budding, and much less frequently by branching. Under the Influence of the external environment and changing living conditions, the morphological, cultural, and biological properties of tuberculosis mycobacteria undergo alterations. They can sometimes form coccoid, granular structures, filterable forms, and L-forms, a phenomenon known as persistence. The transition from persistent forms back to vegetative bacterial forms is called reversion. The Use of antimycobacterial drugs frequently leads to drug resistance in MTB. It is believed that drug resistance, as a form of Variability, arises primarily through the "adaptation" of MTB to antimycobacterial drugs. Under antimycobacterial therapy, point chromosomal Mutations may occur, involving alterations in the ribosomal-matrix system or plasmid DNA of the mycobacteria, which leads to The Emergence of drug-resistant strains. Specific genes have been identified whose mutations confer resistance to individual anti-tuberculosis drugs. On the other hand, every population of drug-susceptible mycobacteria contains resistant mutants that continue to multiply during Chemotherapy, leading to a steady increase in their population. This phenomenon is termed the Selection of resistant mutants. Ineffective Treatment results in the accumulation of mutations targeting specific drugs, which becomes fixed across 2–3 genes.

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Fig. 4. Mycobacterium tuberculosis. Mag. 700x. Ziehl-Neelsen stain

Fig. 5. Mycobacterium tuberculosis under an Electron microscope

Primary and secondary drug resistance are distinguished. Primary resistance is resistance observed in newly diagnosed, untreated patients (up to 25%), resulting from infection with resistant MTB strains. Secondary or acquired resistance is identified in patients who have undergone antimycobacterial therapy for more than 4 weeks; it predominantly arises during irrational therapy and is observed in 75% of treated patients, most commonly in those with chronic forms of the disease.

In accordance with unified international terminology, researchers distinguish mono-resistance (MTB resistance to any single first-line drug: isoniazid, pyrazinamide, rifampicin, streptomycin, or ethambutol), poly-resistance (MTB resistance to two or more first-line drugs), and multidrug resistance (resistance to the combination of isoniazid + rifampicin alongside other first-line drugs). Furthermore, a distinction is made between drug-resistant tuberculosis—tuberculosis caused by MTB strains resistant to one or more anti-tuberculosis drugs—and multidrug-resistant tuberculosis, characterized by MTB strains resistant to at least the combination of the most active anti-tuberculosis drugs: isoniazid + rifampicin.

Pathogenic MTB include: M. tuberculosis, M. bovis, and M. africanum. All of them are highly resistant in the environment; specifically, they survive in soil for 1–2 years, in water bodies for up to 5 months, in street dust for up to 10 days, indoors under diffused sunlight for up to a month and a half, in feces and on pastures for up to 1 year, in butter and cheese stored in a refrigerator for 8–10 months, and on book pages for 3 months. At a Temperature of -20 °C, MTB remain viable for up to 7 years. Boiling liquid sputum destroys MTB within 5 minutes. Exposure to sunlight kills MTB in 1.5 hours, and ultraviolet irradiation kills them within 2–3 minutes.

Atypical (opportunistic) mycobacteria can under certain conditions become pathogenic to humans, causing mycobacteriosis—a disease clinically similar to tuberculosis. Atypical mycobacteria include: M. avium, M. intracellulare, M. scrofulaceum, and others.

In 85–97% of cases, human tuberculosis results from infection with the human MTB species, in 2–15% from the bovine species, and very rarely from the avian species.

The sources of human tuberculosis infection are infected humans and animals that shed MTB. Depending on the affected organ, the pathogen is released into the environment via sputum, feces, urine, milk, semen, etc. Transmission occurs most frequently via the aerogenic route (90–95%), less commonly through alimentary and contact routes, and extremely rarely transplacentally (congenitally). In congenital transmission, fetal infection generally occurs via two pathways: hematogenously, transplacentally, or through the aspiration and swallowing of Amniotic Fluid and mucus from the birth canal in cases of maternal Genital Tuberculosis. In hematogenous intrauterine transmission, MTB pass from the mother to the fetus via the umbilical vein, entering the Liver or the ductus venosus into the right side of The Heart and the Lungs. In transplacental transmission, the primary lesion forms in the fetal liver.

Primary encounter with the tuberculosis infection typically occurs in children, and less frequently in adolescents and adults. MTB that enter the respiratory tract can be cleared from the Bronchi by the mucociliary escalator—the ciliated epithelium—trapped in mucus, which prevents their contact with alveolar macrophages. Alternatively, upon primary infection, MTB encounter polynuclears and phagocytes and undergo phagocytosis. Macrophages are destroyed, releasing MTB, their fragments bound to J-Proteins, and mediator Enzymes (such as interleukin-1) into the intercellular space, which activate T-lymphocytes. The latter, in turn, secrete mediators known as lymphokines (such as interleukin-2) that accelerate macrophage migration and enhance their enzymatic activity against MTB. These mediators also activate B-lymphocytes, which transform into plasma Cells capable of producing IMMUNOGLOBULINS—specific Antibodies directed against MTB Antigens. However, the exact role of humoral Immunity remains incompletely understood. Cell-mediated immunity mechanisms, executed by sensitized T-lymphocytes (specifically their subpopulations and ratios), are of greater importance: T-helper cells activate macrophages, T-suppressor cells suppress them, and T-killer cells can adhere to cells that have phagocytosed MTB and destroy them along with the infectious agent. Substances released during heightened macrophage enzymatic activity promote an inflammatory response, while MTB phosphatides cause macrophages to transform into epithelioid and Langhans giant cells, ultimately forming the tuberculosis granuloma (Fig. 6). Concurrently, T-killers destroy mycobacteria along with macrophages and surrounding Tissues, resulting in caseous necrosis.

Dry caseation typically develops in the center of the tuberculosis granuloma and provides an unfavorable environment for MTB multiplication. The subsequent dynamics of the infectious process depend on the size of the bacterial population and the efficacy of the host immune systems.

When the MTB count is low, as immunity develops, their multiplication slows down, the inflammatory response diminishes, the specific granuloma undergoes sclerosis, and mycobacteria transform into persistent forms that maintain relative acquired immunity. An indicator of this immunological shift is a positive tuberculin Skin test, which appears 3–12 weeks after infection and persists for life. Under certain unfavorable conditions, months or years later, persistent MTB forms can revert to virulent states, triggering a reactivation of the specific inflammatory process and The Development of secondary forms of tuberculosis.

Fig. 6. Tuberculosis granuloma

During intensive multiplication of a large mycobacterial population, T-helper activity decreases, macrophage activation is inhibited, and the number of T-suppressors increases. Gradually, the tuberculosis process progresses, leading to the development of Primary tuberculosis forms. Primary tuberculosis emerges following tuberculin conversion, characterized by pronounced Organism hypersensitivity, mandatory involvement of The Lymphatic system, a tendency for hematogenous and lymphogenous dissemination, frequently accompanied by serous membrane involvement and paratuberculous hypersensitivity reactions.

Review Questions

1. Who discovered the tuberculosis pathogen, and when?

2. Where and by whom was the world's first tuberculosis dispensary established?

3. The significant achievement of French scientists Calmette and Guérin in 1919.

4. Who discovered streptomycin, and when, for which he was awarded the Nobel Prize?

5. When were the most effective antimycobacterial drugs (isoniazid and rifampicin) synthesized?

6. Prominent Ukrainian phthisiatricians.

7. What proportion of the world's population is infected with Mycobacterium tuberculosis?

8. What is the annual global incidence of tuberculosis, and on which continents is it highest?

9. What do you know about the current Epidemiological situation of tuberculosis in Ukraine?

10. What is tuberculosis?

11. The tuberculosis pathogen: its properties and types.

12. The source of human tuberculosis infection.

13. Modes of tuberculosis transmission.

14. The Structure of the tuberculous granuloma.

TESTS

1. In what year did Robert Koch discover the tuberculosis pathogen:

A. 1865

B. 1882 C 1887

D. 1919

E. 1944

2. Which Ukrainian scientist discovered X-rays even earlier than Roentgen:

A. O.A. Kysil

B. B.M. Khmelnytskyi

C. F.G. Yanovskyi

D. I.Ya. Horbachevskyi

E. I.P. Puliui

3. Who was the first to propose artificial pneumothorax for the Treatment of tuberculosis patients:

A. R. Koch

B. R. Philip

C. C. Forlanini

D. A. Calmette and Guérin

E. S. Waksman

4. Who synthesized streptomycin?

A. Fox

B. S. Waksman

C. A. Calmette and C. Guérin

D. C. Forlanini

E. Abbé

5. Isoniazid was synthesized in the laboratory of:

A. S. Waksman

B. Fox C. R. Koch

D. W. Röntgen

E. R. Philip

6. What percentage of the world's population is infected with tuberculosis?

A. 5 %

B. 10 %

C. 15 %

D. 30 %

E. 50 %

7. A patient with Pulmonary Tuberculosis can annually infect:

A. 1-5 people

B. 10-15 people

C. 25-30 people

D. 35-40 people

E. 45-50 people

8. What percentage of individuals infected with MBT develop tuberculosis?

A. 1-2 %

B. 3-4 %

C. 5-10 %

D. 15-25 %

E. 30-40 %

9. The total number of tuberculosis patients in the world is:

A. 3-5 million

B. 10-15 million

C. 20-30 million

D. 40-45 million

E. 50-60 million

10. The world's first tuberculosis dispensary was founded by:

A. R. Koch

B. R. Philip

C. A. Calmette and Guérin

D. Abreu

E. F.G. Yanovsky

11. The BCG tuberculosis vaccine was developed by:

A. R. Koch

B. S. Waksman

C. A. Calmette and Guérin

D. F. Seibert

E. M. A. Linnikova

12. The most probable transmission distance for droplet infection with MTB.

A. Up to 1.5 m

B. Up to 3.5 m

C. Up to 4.5 m

D. Up to 6 m

E. Up to 10 m