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Theme of lecture: Determination of tuberculosis as scientific and practical problem. Phthisiology history. Epidemiology of tuberculosis. Etiology, pathogenesis of tuberculosis. Immunity at tuberculosis. Слайд 1

PLAN OF THE LECTURE1. HISTORICAL REVIEW

2. THE WORLD TUBERCULOSIS EPIDEMIOLOGICAL SITUATION

3. TUBERCULOSIS EPIDEMIOLOGICAL SITUATION IN UKRAINE

4. TUBERCULOSIS EPIDEMIOLOGY

5. TUBERCULOSIS MICROBIOLOGY

6. TUBERCULOSIS PATHOGENESIS

7. TUBERCULOSIS PATHOLOGY

8. CLINICAL CLASSIFICATION OF TUBERCULOSIS

Слайд 3Phthisiology - a science subject of study which are causes, development mechanisms, diagnosis, treatment and prevention of tuberculosis.Tuberculosis - an infectious disease, which is the causative agent of tuberculosis, is characterized by granulomatous-cheesy and necrotic tissue-destructive impressed with the wide clinical polymorphism, showing social dependency, causing temporary and permanent disability and requires long-term comprehensive treatment and rehabilitation. Term: TB - is derived from the Latin. words tuberculum - bump and in fact shows the morphological manifestations of the disease (G. Laenek, H. Virchow).Word phtisio (phthisis) - is of Greek origin and is translated as tuberculosis, consumption, emaciation, cachexia, which shows the clinical manifestations of the disease.HISTORICAL REVIEW Слайд 4, 5 Tuberculosis, as an illness, is known since ancient times. The principal clinical manifestations of tuberculosis are described still by Hippocrate, Gallen, Avizenna. The fact that tuberculosis is infectious disease was confirmed by Fracastoro in the 16th century. It was Morton who published the first monography "Phthisiology or a treatise on the phthisis" (R. Morton, 1689) and named a science of tuberculosis "phthisiology" (from the Greek word "phthisis" -which means exhaustio. In the 17th century the French anatomist Sylviy, describing the hurt lungs of patients who had died of phthisis, used the word "hump" (tuberculum). However, it was only in the 19th century in France that pathologists and therapeutists G. Bayle, and then R. Laennec proved the hump and caseous necrosis to be specific morphological substratum of tuberculosis. In 1865 the French physician B. Villemin experimentally proved the infectious nature of tuberculosis, though he could not reveal the pathogene. In 1882 the German bacteriologist Robert Koch (fig. 1) discovered the pathogene of tuberculosis, which was named bacillus of Koch (BK). He was also the first who obtained tuberculin with the hope to successful treatment of tuberculosis patients. These expectations of the scientist did not come true, nevertheless for the purpose of diagnostics tuberculine has been used for over 100 years. M.I. Pyrohov studied clinico-morphoiogical properties of tuberculosis of various localization and for the first time described typhoid form of miliar tuberculosis, histologic structure of tuberculous granuloma. Further study of pathomorphologyl alterations at lungs tuberculosis was proceeded by A.I. Abrykosov and A.I. Strukov.

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In 1887 R. Philip in Edinburgh (Scotland) founded the world first antituberculosis dispansery. This new institution offered the patients not only medical but also social help, which later on laid the foundation of the organization of antituberculosis service also in this country. In 1882 in Rome C. Forlanini offered artificial pneumothorax for treating lung tuberculosis patients. In 1895 Wilhelm Kondrat Roentgen discovered X-rays, which have been widely used in medicine up to today. Actually, it's known well enough that X-rays were discovered by Ukrainian scientist Ivan Pulyuy (1845-1918) from Halichina 17 years earlier. However, he made his announcement about the discovery 7 days after Mr. Roentgen had made his one, thus the preference was given to Mr. Roentgen who received Nobel Prize. In 1909 the first free hospital for tuberculosis patients was opened in Moscow. An important achievement of the start of the 20th century was the creation by the French scientists Calmette and Guerin (1919) of the antituberculosis vaccine BCG (Bacilles Calmette, Guerin). Since 1935 mass vaccination began. At the same time in 1924 Abre in Brazile introduced the method of fluorographic observation of the population for active revealing lung tuberculosis patients. In 1944 the American bacteriologist from Odesa S. Waksman obtained streptomycin, for which he was awarded the Nobel Prize (1952). PASA, tibon, GINA preparations (the most effective of them -isoniazidum, synthesized in Fox's laboratory. GB, 1951) came into practice somewhat later, and since 1965 rifampicinum, the most effective antimycobacterial medicine has been used. A noted contribution into the theory and practice of the national phthisiology belongs to F.G. Yanovsky, who organized the first bacteriologic laboratory in Kyiv and the first health resorts, improved the clinical methods of examination. In 1922 Kyiv Tuberculosis institute was founded on the basis of the 9th city tuberculosis hospital (Kyiv, Otradna Str. 32, today Manuilsky street). Prof. F.G. Yanovsky was the initiator of its foundation and the institute scientific council head. Our countrymen A. A. Kysel, O.S. Mamolat, M.M. Amosov, M.S. Pylypchuk, B.P.Yaschenko, Yu.I. Feschenko, V.M. Petrenko, V.M. Melnyk (Kyiv), B.M. Khmelnytsky, A.H. Khomenko (Kharkiv), I.T. Stucalo, Y.V. Kulachkovsky (Lviv) may be rightly named the coryphaei of phthisiology.

Слайд 6 THE WORLD TUBERCULOSIS EPIDEMIOLOGICAL SITUATION More than 6 billion people live on our planet now. More than 2 billion of them suffer from various diseases. Every fifth earthman lives in extreme need and poverty, which has become the main death reason in the world. Today tuberculosis is the most widely spread infectious disease which ranks first as to the deathrate among the people from infectious pathology. Moreover, new misfortunes are added. In 2001 A.D. there are 30-40 million carriers of the human immunodeficite virus in the world and 10 million AIDS patients, who increase the number of tuberculosis patients considerably. According to the data of the World Health Organization half of the globe population is infected with tuberculosis mycobacteria. In some countries infectiousness of the population with tuberculosis reaches 80-90 %. 1 his is also true about Ukraine. Every year each tuberculosis patient can infect 10-15 and more persons of which 5-10 % will catch the disease. Every year 7-10 million people fall ill with tuberculosis all over the world, including 4-4,5 mln. - with bacterial secretion and about 3 mln. adults die of it (of these 97 % - in the developing countries) and approximately 300 thousand children. The total number of tuberculosis patients reaches 50-60 mln. Nowadays tuberculosis is the most menacing illness forthe whole mankind. It kills more patients worldwide than all the infectious and parasitic illnesses taken together. Present tuberculosis epidemic has acquired the global scales. In many parts of the world tuberculosis epidemic is beyond the control. The highest tuberculosis statistics of sickness is noted in African and Asian regions, in the countries of the Pacific Ocean coast. Tuberculosis epidemic situation got worse in the countries of Europe too, especially in the countries of the former Socialist community. In 1998 the lowest tuberculosis index was registered in the highly developed countries, such as Malta (4,2), Sweden (5), Norway (5,5), Iceland(6,2), Italy (8,4 per 100000 of the population), the highest- in Romania (114,6), in the former Soviet Union, as in Kyrgystan (127,8), Kazakhstan (126,4), Georgia (124,4), Turkmenistan (86,1 per 100.000 of the population). Tuberculosis causes great danger for the human race. The worsening of the epidemiological situation of tuberculosis, which is now the most spread infectious disease in the world, marked the last decade of the 20th

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century. According to a WHO report, one third of the world population (1.9 billion people) are already infected with Tb, which leads to a possible increase of the incidence rate of tuberculosis associated with HIV infection epidemic. In some countries, including Ukraine, infection rate mounts to 80-90 % . Every second someone is infected with tuberculosis on our planet. It is estimated that one tuberculous patient can infect 10-15 healthy individuals per 100,000 people. Every year 7-10 million new tuberculosis cases are detected, including 4-4.5 million with sputum positive disease. Tuberculosis “is responsible" for 3 million adult deaths and 300,000 children's deaths per year, 97 % of them in developing countries. Tuberculosis causes more deaths than all infectious and parasitic diseases taken together.The highest tuberculosis incidence rate is now seen in Africa, Asia, and Pacific coast countries. Tuberculosis epidemiology is worsening in Europe, especially in Eastern Europe, where the increase of mortality caused by tuberculosis has been predicted. According to the WHO, all European countries have been divided into three groups by tuberculosis incidence rate:-countries with a low incidence rate (less than 10 cases per 100,000 people): Austria, Czech Republic, Germany, Greece, Norway, France, Switzerland, Sweden, etc.;- countries with a medium incidence rate (10-30 cases per 100,000 people): Bulgaria, Hungary, Poland, Turkey, Spain, and Portugal;- countries with a ыыhigh incidence rate (more than 30 cases per 100,000 population): all the countries of the former Soviet Union and Romania. It is estimated that between the years 2000-2020 there will be about 1 billion infected, 200 m symptomatic disease patients, and over 40 m will die of tuberculosis if tuberculosis control does not become more effective. Due to such risk the WHO announced tuberculosis "a global emergency" (WHO Program on tuberculosis. Structure for effective control of tuberculosis. - Geneva: WHO,1994.-p. 15). Not one country can afford to ignore the problem of tuberculous because it threatens public health, economy growth, and future development of the society. The high incidence rate and mortality rate of tuberculosis most often reflect inadequate measures of infection control and ignoring of the disease. According to the WHO, most often the causes for the relapse of tuberculosis epidemic are: - ignoring of the disease by governments of many countries lead to the decline or even liquidation of tuberculosis control in these countries; - inadequate administration and incorrect programming of tuberculosis control promoted the increase of incidence rate and multiple drug resistant Tb; - population growth and migration promote higher incidence rate; - association of tuberculosis with HIV infection caused dangerous tuberculosis morbidity in HIV infection endemic areas.Слайд 7 TUBERCULOSIS EPIDEMIOLOGICAL SITUATION IN UKRAINE If one looks into the past, he will see that from 1965 to 1990 the morbidity i 'fall clinical forms of tuberculosis decreased 3,6-fold or from 115,4 per 100 thousand population to 32,0 per 100 thousand population; the death-rate for these years decreased 3,3-fold or from 27,1 per 100 thousand population to 8,l per 100 thousand population. However, starting from 1990 a crucial moment occurred in tuberculosis epidemiological situation, it started to grow, which is vividly reflected in epidemiological indices. The epidemiological situation of tuberculosis is assessed according to the following indices: statistics of sickness, morbidity, death-rate and infication. The statistics of morbidity in all forms of tuberculosis in Ukraine from 1990 to 2003 increased from 32 to 77,5 per 100 thousand population or 142,2 %. In 1999 there were 679671 tuberculosis patients in Ukraine, or 1,4% of the whole population. Tuberculosis process is subjected to the general laws of the epidemiological process, it appears and is supported only under the condition of interconnected three main links: the pathogene source, the mechanism of its transmission and the organism's receptivity to tuberculosis. In Ukraine under present conditions of tuberculosis epidemic the tuberculosis infestation of children aged 7-8 is 9 % and those of 13-14 -20 %. In the age group under 40 the infestation is 80-90 %. Thus, tuberculosis infestation of population differs and it increases from year to year. It depends upon many factors: the level of

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the population tuberculosis sickliness, living conditions, general and sanitary culture of the population, active tuberculosis fight in the country. At the same time, the WHO experts dream and suggest the following criteria of liquidation of tuberculosis as a wide-spread illness: revealing not more than one patient with bacterial extraction per ten millions population per year, the total statistics of sickness up to 20 per 100 thousand population and infestation of 14-yearolds - not more than 1 per cent.Слайд 8 TUBERCULOSIS EPIDEMIOLOGY. Epidemiologic features of tuberculosis include: infection rate, incidence rate, morbidity, mortality, infection risk, and infectiousness parameter. Infection rate is the percentage of positive tuberculin skin test cases divided by the total number of the examined, excluding persons with post-vaccination immunity. Infection rate is determined by Mantoux test with 2 international units (IU) of the international standard of purified protein derivative (PPD-L). This parameter characterizes the reservoir of tuberculosis infection. Infection rate does not always correspond to morbidity because morbidity decrease gets ahead of infection decline. Infection rate increases with age. It is higher by 5-10 % in urban population as compared to rural population. According to Y.I. Feshenko (2002), tuberculosis infection rate in Ukraine is 8.5 % in children of 7-8, 19.5 % in children aged 13-14, and 80-90 % in adults younger than 40. An important role in infection rate decrease belongs to the treatment of tuberculous patients and achievement of abacterial state. The effectiveness of infection control is more accurately measured by infection risk, or infection rates accretion. Infection risk is the accretion of infection cases in a given year. This parameter should not exceed 1 %. If infection risk exceeds 2 %, then 90 % population will be infected by the age of 70.The effectiveness of tuberculosis control is also measured by infectiousness parameter, which is the number of persons, who can be infected by one patient with the clinically active disease. With well-organized infection control infectiousness parameter should not exceed 10. Incidence rate is the number of new cases with the clinically active disease per 100,000 people in a certain region in the given year. Morbidity is the number of old and new cases with the clinically active disease per 100,000 people in a certain region in the given year. The dynamics of incidence rate is studied by means of comparing one from previous years with one from other administrative territories. Other parameters used in statistics are the incidence of disease location and the incidence of pulmonary and extrapulmonary tuberculosis. Incidence rate is influenced by infection massiveness and duration. Household contacts in unfavorable socioeconomic conditions promote infection. This explains the high frequency of superinfection among people contacting in everyday life and at work. The latter is quite often observed among medical personnel of TB dispensaries. Environmental factors also influence incidence rate. Acclimatization has a negative effect on incidence, usually when an individual moves from south to north. The incidence among migrating population is 2-4 times higher than among non-migrants. The incidence among population living in mountains is lower than among population of valleys. Incidence is higher in humid and cold climates. Balanced diet is important: tuberculosis incidence is higher among individuals with the nutritional deficiency of animal protein. Incidence varies in different age groups: only rarely individuals in early childhood and adolescence have tuberculosis. Middle-aged men are infected 2-3 times more often than women in the same age group. In the last years the incidence of tuberculosis among the elderly has increased. Other diseases negatively influence the incidence rate of tuberculosis. There are such high-risk segments of population: people having close contacts with tuberculous patients; newly discovered cases (especially tuberculin hyper-reactors); recent convalescents; individuals with diabetes mellitus, gastric and duodenal ulcer, silicosis; alcohol and drug addicts; HIV-positive people; individuals undergoing immunosuppressive therapy of systemic corticosteroids; migrants; elderly people; the homeless; prisoners or released from prisons; persons with various occupational dangers. Mortality is the number of deaths assigned to tuberculosis per 100,000 people of the given region during a year.

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Mortality and morbidity depend on the effectiveness of treatment; infection and incidence rate depend on the effectiveness of prevention. Infection rate, incidence rate, morbidity, and mortality are all associated with socioeconomic factors. In all countries of the world tuberculosis morbidity and mortalily are 2-3 times higher among men than among women. This difference is negligible in children. Lethality of tuberculosis is the ratio of deaths caused by tuberculosis to the number of patients registered in a TB dispensary during a year.Слайд 9 TUBERCULOSIS MICROBIOLOGY The incidence and course of tuberculosis are determined by causative agent characteristics, human body reactivity, and socio-economic factors. The causative agent of tuberculosis is Mycobacterium tuberculosis (Tb), the older name is Koch's bacillus.On March 24, 1882, R. Koch demonstrated the pure culture of the causative agent under the microscope; infection of animals proved its contagious nature. For this reason the microbe was named after Koch (BK stands for bacillum Kochii). It is noteworthy that another German scientist - Baumgarten - demonstrated the tuberculosis bacillus cultured from a contaminated rabbit on March 18, 1882, but he did so only under the microscope.The causative agent of tuberculosis belongs to Mycobactrium species, Actinomycetales order, Schizomycetes class. Representatives of Mycobacterium species also cause leprosy, many of them are saprophytes found in smegma, cerumen, sputum from bronchiectasis. They are also acid-fast microbes vegetating on mucosal surface, batter, milk, plants, in water, soil, etc.By contagiousness for man and animals Mycobacterium species are divided into two groups: the first group is pathogenic tuberculosis bacteria proper subdivided into three types: M.tuberculosis causing tuberculosis in man, M.bovis causing bovine tuberculosis, and M.africanum; the second group is atypical Mycobacterium species with saprophytes (nonpathogenic for man and animals) and opportunistic pathogens (under certain conditions they might cause mycobacteriosis, a tuberculosis-like disease).Tuberculosis in man is usually caused by the human species of Mycobacterium (95-97 %), much rarer by the bovine, and only sporadically by the avian species of Mycobacterium. M.africanum causes tuberculosis in the countries of tropical Africa and is seen as the intermediate species between M.tuberculosis and M.bovis.Tb are straight or slightly curved rod-like round-ended nonmotile cells 1.0-10.0 pm long and 0.3-0.6 pm in diameter; produce neither spores nor capsules; Gram-positive; can be very polymorphous. The human Mycobacterium species are more slender and longer than the bovine ones. Niacin test is used to detect the human Mycobacterium as these produce more niacin then the bovine ones. Young bacteria are homogenous, but with ageing or due to antibacterial therapy they acquire granules (Mucha's granules), which are visualized in more details by means of electronic microscopy. Introduction of these granules into animals causes cachexia, lymph node enlargement or tuberculosis clinical signs.Fragmented, filtered, and L-shaped Mycobacteria are also described (Fontes, 1910) Under the influence of antituberculous medication the morphology, physics, and chemistry of Mycobacteria may change. The conversion of the bacterial form of Mycobacteria into fragmented, filtered, or L shaped ones is called persistence, The return of persistent forms into bacterial is called reversion.Слайд 10 – 11 Characterization of Mycobacterium tuberculosis (MBT ) The chemical composition of Tb is well studied: they consist of 80% water and 2 3 % lime. Solid residue consists of 50 % protein, mostly tubercular proteins, 8-40 % lipids, and about the same percentage of polysaccharides. Tubercular proteins have been suggested to be complete antigens able to cause anaphylaxis in animals.Mycobacteria resistance is provided by fat content; polysaccharide fraction plays a role in immunogenesis. Tubercular proteins and lipid fractions are responsible for the toxicity of Mycobacteria,which they retain even after having been killed. High fat content gives Mycobacteria the following properties: 1. Fastness to acids, alkalis, and alcohol (mostly due to mycolic acid content). 2. Resistance to basic disinfectants. 3. Pathogenicity. Exotoxins have not been detected in Mycobacteria, but the cells themselves are toxic, loading to partial or entire leucocyte disintegration. The antigen composition of Mycobacteria is complicated and not well

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understood. Different strains have different antigens. Commonly present antigens in all Mycobacteria are polysaccharides, which are also responsible for bacterial resistance to heating and proteolytic enzymes.

The construction of the MBT cell wall consists in several layers.  External layer (description top down) contains lipids. The primary frame of the cell wall consists in peptinoglycans. The layer of arabinolactans has points of connection with the layer of peptidoglycans and structures for  fastening mycolic acids and their derivatives. The mycolic acids presents in a form of free sulfolipids and cord-factor. The layers of cell membrane and layers of cell penetrated be channels and pores providing  controlled diffusion and transport of energy dependent substances. Terminal fragments  unspecifically suppress activation of T-lymphocites and leucocytes of peripheral blood. This process cause disturbance of immune reaction of the host on mycobacterium. Beneath the cell wall there are three layers of cytoplasm membrane closely adjacent to the cytoplasm. Mycobacterial cytoplasm is homogeneous and contains granules, microgranules, and vacuoles. Most granular inclusions are ribosomes consisting of RNA and protein and synthesizing Mycobacterium's protein. Mitochondria, Goldgi complex, and lysosomes are absent in the cytoplasm. Слайд 12 Atypical Mycobacterium Species. E.N. Runyon divided these into four groups based on their growth rate and pigment formation:- the Ist'group (photochromogeneous bacteria) produce lemon-yellow pigment on exposure to light; it takes 2-3 weeks for a colony to grow. The representatives are M.kansasii, M.marinum;- the 2nd' group (scotochromogeneous bacteria) produce yellow-orange pigments in the dark or on exposure to light. The representatives are M.aquae, M.serofulaeeum;- the 3rd' group (nonphotochromogeneous bacteria) produce weak or no pigment; it lakes 5 10 days for a colony to grow. The representatives are M.avium, M.intracellulare, M.xenopi, M.haemophilum;- the 4th group (rapidly growing bacteria) forms a colony in 2-5 days. These are predominantly saprophytes (M.phlei, M.smegmatis, M.fortuitum).Слайд 13 There are three types of mycobacteriosis singled out by the type of Mycobacterium and the host's immune status:1.Generalized infection with macroscopic signs similar to I hose of tuberculosis, but different from it microscopically. There is a diffuse interstitial alteration in the lungs without granuloma or caverna formation. The clinical signs are fever, dissemination in the middle and lower segments of both lungs, the patients are anemic and neutropenic. Other symptoms include diarrhea and abdominal pain. The diagnosis is proved by the causative agent culture from sputum, feces or by means of biopsy. Mycobacteriosis is difficult to treat. Effective preparations include cycloserin, ethambutol, kanamycin, rifampicin, and sometimes streptomycin. 2. Localized infection is characterized by micro- and macroscopic local alteration in the host.3. Infection without visible signs. The causative agent is harbored in the lymph nodes.Слайд 14, 15 TUBERCULOSIS PATHOGENESIS. The chief reservoir of infection is man with the destructive disease type. Also, to a lesser extent, domestic animals can be the source of infection.Depending on the portal of entry Tb may first enter the lungs, tonsils, bowel, etc .The presence of Tb in these tissues is not evident at first because they produce no exotoxin and their phagocytosis is limited. Mycobacteria remain extracellular and replicate slowly; surrounding tissues remain unchanged, pathological changes are absent. The state when the host is tolerant to Tb is described as latent microbism. Quite soon Tb enter regional lymph with the lymph flow following their spread through the lymph and blood flow in the host independently of the portal of entry. This is primary obligate microbacteriemia. Mycobacteria settle in organs with the best microcirculation: the lungs, lymph nodes, renal cortex, long bones' epiphyses and diaphyses, and the uveal tract. Settled Tb reproduce themselves. They may grow into a big population before immunity is formed for their effective destruction and elimination. Phagocytosis - unspecific defense reaction - starts at the location of mycobacterial population. The first phagocytes attempting to digest and destroy Tb are polynuclear leucocytes. However their bactericidal potential is insufficient for defense. The polynuclear leucocytes contacting Tb die. Macrophages interact with Tb after polynuclear leucocytes. The first phase of the interaction is Tb fixation on the macrophage cell wall with special receptors. The next phase is Tb ingestion. A portion of plasmolemma gets deeper into the cytoplasm forming a phagosome containing Tb. The third terminal phase is associated with

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phagolysosome formation from the merging of the phagosome and macrophage's lysosome. Under these conditions proteolytic enzymes can destroy the engulfed Tb. Tb may also persist and even multiply in macrophages. Tb entrance and multiplication in a cell is called Infection. Tb can produce substances harmful to the host. Macrophages die and Tb spread outside the cell again. Such interaction of macrophages and Tb is called incomplete phagocytosis. Following that, Tb may cause such morphological changes as paraspecific reactions. Hystio-macrophageal or lymphoid infiltrates are formed at this stage. These either dissolve or develop into tubercles. The merging of the latter cause the spread of tubercular inflammation to the regional lymph nodes. With present pathological changes but absent clinical disease the condition is called latent infection. Immunity against tuberculosis (positive tuberculin skin test) develops before the local pathological signs of infection. The period of time from the contact of Mycobacteria with the host until the development of positive tuberculin skin test is called premunity period. This period coincides with the period of latent microbism and lasts 4 to 8 weeks on average, but it can be as short as 8-10 days and as long as 11 months. The period of time after the development of positive tuberculin skin test is called immunological period. Tuberculin skin test is thus an immunological test and the emerging tuberculin skin test is called virage (positive tuberculin skin test). Primary tubercles dissolve, consolidate, and calcify or develop into different types of primary tuberculosis. Clinical and radiological recovery of a patient with primary tuberculosis does not always lead to Mycobacteria elimination from the host; clinical recovery does not always mean biological recovery. For instance, virulent Tb or their L-shaped forms were found in the lymph nodes of the patients, whose cause of death was unrelated to tuberculosis. Latent microbism and latent infection can cause secondary tuberculosis. Secondary tuberculosis develops due to poor defense mechanisms of the host, exacerbation in the foci of primary infection (endogenous reactivation) or exogenous superinfection (additional infection).Слайд 16 Primary infection starts with the transmission of virulent Tb to the host. In most cases primary infection does not cause the disease due to the adequate protection of the host. Low immunity and a high dose of highly virulent Mycobacteria promote primary tuberculosis even with primary infection, which usually completes with the destruction and elimination of the majority of Tb. Small Mycobacteria populations are capsulated in the course of residual changes. If the host fights Tb successfully and no disease occurs, these residual changes are only microscopic. The changes taking place after latent infection reactivation are more significant; these can be found on radiology films. Antituberculous immunity is formed during primary infection. The clinical forms of primary tuberculosis are: tuberculosis of unknown primary site, tuberculosis of intrathoracic lymph nodes, and primary tuberculosis complex. Primary infection of man with Tb usually happens via the respiratory tract (aerogenic way). Other modes of transmission (alimentary, contact, transplacental) are observed much rarer. In the aerogenic infection with Tb mucociliary clearance plays a defensive role. The mucus produced by the goblet cells pastes Mycobacteria together in the respiratory airways. Synchronic movements of epithelial villi and wave-like contractions of the bronchial and tracheal walls promote the elimination of Mycobacteria from the respiratory tract. This universal defense mechanism can be very effective, in many cases it may prevent infection after a short episodic contact with a patient actively releasing Tb. Despite infection in such cases the likelihood of tuberculosis disease decreases. Acute or chronic inflammation in the upper respiratory tract as well as intoxicants might result in defective mucociliary clearance and promote the passage of Tb into the bronchioles and alveoli. Under these conditions the likelihood of aerogenic infection with Tb and the development of clinical symptoms of tuberculosis is increased.

Слайд 17,18,19 Morphology of TBCSpecific inflammation reaction to tuberculosis is classical immunological inflammation. The main morphological element of tubercular inflammation is a tubercle, often called a tubercular granuloma. A distinctive feature of a tubercular granuloma is central cheesy or caseous necrosis -dense amorphous cell detritus consisting of dead phagocytes. The zone of caseous necrosis is surrounded by several layers of epithelioid cells, macrophages, lymph and plasma cells. Great multinuclear Pirogov-Langhans' cells

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can be found among epithelioid cells. The cells around the zone of caseous necrosis form granulation tissue. These cells may be dystrophic and destroyed. Specific inflammation involves parenchyma cells, lymphatics, and blood vessels of the affected organ. In the course of pulmonary tuberculosis specific inflammation also involves the bronchi. Tuberculosis is said to be a granulomatous disease due to its immunological and pathological features of specific inflammation. The function of the affected parenchyma cells is significantly compromised due to their dystrophy and destruction. The draining function of lymphatics is decreased as lymph enters the intercellular space due to the damaged endothelium of the lymphatic vessels. Thrombosis of small blood vessels leads to microcirculation compromise: blood vessels are damaged due to the fixation of circulating immune complexes to their basal layer as can be seen under the electronic microscope. There are almost no blood vessels in the tubercular granuloma: nutrients are supplied to granuloma cells by diffusion from the extracellular fluid. Granuloma cells change as the granuloma undergoes formation stages. According to the type there are epithelioid cells, lymph cells, and giant cells. In cases when necrosis is prevalent the granuloma is said to be necrotic. The character of cell reaction determines the cell content of a granuloma and necrosis prevalence. Epithelioid, macrophage, and multinuclear giant cells are prevalent in productive cell reaction. The outer cell layer has fibroblasts synthesizing collagen. There is little or no necrosis at the center of such a granuloma. Larger ne-crosis is seen in exudation cell reaction: necrosis takes from 30 % to 50 % of the granuloma. Macrophages and lymph cells are prevalent in the cellular layer but a limited number of epithelioid and giant cells can also be seen in such a granuloma as well. Alteration cell reaction features prevalent necrosis and a weak or absent cel-lular layer of the granuloma. Prevalent exudation tissue reaction signifies tubercular Inflammation progression. Serum and fibrin infiltrate the tissues surrounding granulomas. The latter gradually merge into tubercular focus, a pathologic formation up to 1 cm in diameter. Foci progress as inflammation spreads; the latter can be serous, fibrinous or suppurative from the start. Then appear new tubercular granulomas with prevalent central necrosis surrounded by a layer of few epithelioid and giant cells being the signs of specific inflammation. The progressive merging of tubercular foci results in the formation of tubercular infiltrates with caseous necrosis foci, followed by the infiltration of caseous masses with polynuclear leucocytes. Caseous masses melt under the influence of proteolytic enzymes from leucocytes leaving disintegration cavities, which later may transform into caverns. A sharp decline of cell-mediated immunity leads to the fast progress of pathological process resulting in necrotic granuloma formation. Quite soon large foci of caseous necrosis are formed in the affected organ. The intensity and succession of inflammatory tissue reactions (proliferation, exudation, alteration) are highly dependant on the number and virulence of Tb entering the host. Experimental data show that a tubercular granuloma forms in the lung of a dog after the seeding of 10 Tb, a large focus - with 106 bacilli - and a cavern forms after the seeding with 108bacilli. Exudation and alteration reaction dominates with larger mycobacterial population, higher bacterial virulence, higher cellular sensitivity to Tb associated with phagocytosis failure. Such conditions combined with the absence of medical treatment lead to a progressive disease, often with a lethal outcome. The involution of tubercular inflammation is in most cases associated with gradual infiltrate dissolution, a denser zone of caseous necrosis and the formation of a connective tissue capsule around the tubercular granulomas and foci. The infiltration of granuloma foci with collagen, which forms fibroblasts, plays a large role in the healing and scarring of granulomas; hyalinosis completes the healing. Exudate dissolution and tubercular granulations transformation into connective tissue may lead to the fibrosis (cirrhosis) of the affected organ. The absence of specific granulation tissue in the localized foci is a pathology and a clinical sign of recuperation from tuberculosis with the formation of residual posttuberculous changes. These changes can take different forms, for instance a scar, an encapsulated or calcified fibrotic focus, or an area of focal or diffusive pneumofibrosis. In some cases tubercular inflammation ends with the formation of "sanitized" disintegration cavities. Residual posttuberculous changes contain metabolically inactive Tb between fibrotic fibers. The changes are the reservoir of endogenous tubercular infection; they support antituberculous immunity and might cause tuberculosis relapse.

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Слайд 20. Tb immunogenicity is determined by the antigenic complex of Mycobacteria cell wall as well as thermolabile ribosomes fraction. Pathogenicity is the capability of Mycobacteria species to cause diseases. The basic factor of pathogenicity is toxic glycolipid cord factor, which is toxic to tissues and protects Mycobacteria from phagocytosis. Because of this, Mycobacteria propagate even in phagocytes, leading to their death. Acid-fast saprophytes are not characteristic of the cord factor. Virulence is the degree of pathogenicity and capability of Mycobacteria to grow and develop in the host, causing specific organic changes. Mycobacterium strain is said to be virulent if 0.1-0.01 mg of it causes clinical symptoms of tuberculosis and death of a 250-300 g guinea pig in 2 months. If the animal dies in 5-6 months, the strain is said to be weakly virulent. Virulence is not a constant property of Mycobacteria: it decreases with culture ageing, growth on nutrient media, and due to antituberculosis treatment. Passage on animals or disease exacerbation leads to virulence increase. Genetics and mutability. Chromosomes and plasmids are genetic information carriers in Mycobacteria. The main difference between chromosomes and plasmids is in their size: a plasmid is much smaller than a chromosome, thus the former carries much less genetic information. Due to its smaller sizes plasmid is well suited for genetic information transfer from one cell to another (A.G. Khomenko, 1996). Слайд 21. Secondary infection {secondary tuberculosis) develops in two ways: repeated infection with Tb of the primary infected patient {exogenous superinfection) or reactivation of residual posttuberculous changes formed at the end of primary infection (endogenous reactivation). Low cellular immunity caused by unfavorable internal and external factors is an obligatory condition for the development of secondary tuberculosis. A favorable course of secondary tuberculosis leaves posttuberculous changes, whose morphology is different from those of primary infection. According to classification, the clinical forms of secondary tuberculosis are: disseminated, focal, infiltrative, caseous pneumonia, tuberculoma, fibrocavernous tuberculosis, and cirrhotic tuberculosis. Several forms of the disease have a peculiar course that does not fit into the scheme of either primary or secondary tuberculosis. These are said to he post-primary tuberculosis. It may develop with the progress of primary tuberculosis or as a result of the reactivation of residual posttuberculous changes after primary tuberculosis. Disseminated tuberculosis forms are regarded the post-primary type.Слайд 22 CLINICAL CLASSIFICATION OF TUBERCULOSIS Tuberculosis is found under five paragraphs in the International Statistical Classification of Diseases and Related Conditions (10-th edition):A 15. Respiratory organs tuberculosis confirmed by bacteriology or histology.A 16. Respiratory organs tuberculosis unconfirmed by bacteriology or histology.A 17. Tuberculosis of the nervous system. A 18. Tuberculosis of other organs. A I 9. Miliary tuberculosis. In Ukraine a new tuberculosis classification was introduced by the order of the Ministry of Public Health of Ukraine No. 499 of November 28, 2003. This classification takes into account: 1) the type of tuberculosis; 2) the clinical form of tuberculosis; 3) tuberculosis characteristics; 4) complications of the disease; 5) clinical and dispensary follow-up of the patient; 6) effectiveness of the tuberculous patient treatment; 7) outcome of the disease. This classification is adapted to the international tuberculosis classification.Слайд 23 The type of tuberculosis.1.New cases - was first diagnosed tuberculosis ( FDTB ) in patients who had never suffered from tuberculosis or treated with TB least 1 month. Newly diagnosed patient can have both negative and positive results of sputum microscopy and of cultural studies. Such patients may be diagnosed TB various locations.

2. Repeated instances of treatment - in patients previously treated with one month or more from positive or negative bacteriological results of any localization of tuberculosis. Includes the following incidents TV:

2.1. Relapse of tuberculosis ( RTB ) - confirmed case of TB in a patient who had previously successfully completed a full course of antimycobacterial therapy and was considered cured or finished the main course of treatment outcome "treatment completed ", and he returns of bacteria .

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2.2. Treatment after a break ( TAB ) - a case where TB patients interrupted treatment for more than 2 months in a row to complete OKHT who started treatment again regardless of whether the remaining smear positive sputum or gave a negative result. (see Section A.3.3.9 . ).

2.3. Treatment failure ( TFTB ) - a case of TB in a patient who remains or appears bacteria ( smear or seeding ) and / or negative clinical and radiological dynamics ( excluded if another etiology of the disease ), after the standard IF, which if necessary, can be extended by decision CDC maximum of 90 doses. 2.4. Other (OTB) - a TB patient who does not qualify for other types of patients (patients for which no data on prior treatment and its outcome; previously treated patients with pulmonary TB with negative results of sputum microscopy, previously treated patients with extrapulmonary TV with negative results of bacteriological studies, patients with long-term (chronic) course with numerous TV episodes inefficient (interrupted) treatment history of M +).

3. Transferred (arrived) - a patient who was transferred (arrived) in another administrative area (region), or other departments and registered for further treatment.

4. Chemical resistant tuberculosis ( CRTB ) - a form of TB in which the patient identifies Mycobacterium tuberculosis resistant to one or more ATD , as confirmed by laboratory method in DST .There are the following types of drug resistance of Mycobacterium tuberculosis :

4.1 Confirmed mono resistance - a TB in patients with proven MBT isolated in vitro resistance to other POPs and series.

4.2 Confirmed polyresistance - a TB in patients with proven MBT isolated in vitro resistance to more than one and a number of ATD , except for simultaneous resistance to isoniazid and rifampicin.

4.3 Confirmed multi resistance - a TB in patients with proven MBT isolated in vitro resistance of Mycobacterium tuberculosis to at least isoniazid and rifampicin.

4.4. Enhanced drug resistance - resistance of Mycobacterium tuberculosis to both isoniazid, rifampicin , and one of the drugs of 2 groups ATD II series - aminoglycosides and fluoroquinolones.

Слайд 24 Clinical forms of tuberculosis.A15-A16 Pulmonary tuberculosis (PTB) (with a facultative indication of the form of the disease):A15-A16 Primary Tubercular Complex A15-A16 Disseminated Pulmonary Tuberculosis A15-A16 Focal Pulmonary Tuberculosis A15-A16 Infiltrative Pulmonary Tuberculosis A15-A16 Caseation Pneumonia A15-A16 Pulmonary Tuberculoma A15-A16 Fibrocavernous Pulmonary Tuberculosis A15-A16 Cirrhotic Pulmonary TuberculosisA15-A16 Pulmonary Tuberculosis Associated with Occupational Dust Disease (Coniotuberculosis)A15-A18 Extrapulmonary tuberculosis (EPTB) (with an indication of localization):A15-A16 Extrapulmonary Tuberculosis of the Bronchi, Trachea, Larynx, and Upper Respiratory TractA15-A16 Intrathoracic Lymph Node TuberculosisA15-A16 Tuberculous Pleuritis (including empyema)A17 Neurotuberculosis and Meningeal TuberculosisA18.0 Tuberculosis of Bones and JointsA18.1 Genitourinary TuberculosisA18.2 Peripheral Lymph Node TuberculosisA18.3 Tuberculosis of the Bowels, Peritoneum, and Mesenteric Lymph NodesA18.4 Tuberculosis of Skin and Subcutaneous FatA18.5 Eye TuberculosisA18.6 Ear Tuberculosis

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A18.7 Adrenal TuberculosisA18.8 Tuberculosis of Other OrgansA19 Miliary TuberculosisA18 Tuberculosis of Unknown Primary SiteСлайд 25, 26, 27. III. Characteristics of Tuberculosis.The chief parameters characterizing tuberculosis are localization, distribution, destruction (as a stage of the disease) and the roof of bacterioexcretion. 1. Localization. Tuberculosis is localized according to the affected pulmonary segment or lobe; in other organs it is localized according to the anatomical location of the disease. Most often tuberculosis affects the 2nd

(posterior) segment corresponding to the lateral subclavicular area, then the 1st (apical) and the 4th (upper) segments of the lower lobe. 2. Destruction is the destroying of tissue by tuberculosis followed by cavity formation; is detected during X-ray examination. In the diagnosis, (DESTR+) means the presence of destruction, and (DESTR-) means the absence of destruction. The phase of infection may also be included in the diagnosis:• infiltration, destruction (DESTR+), seeding;• resolving, consolidation, scarring, calcification.In filtration, destruction (DESTR+), and seeding characterize the activity of tubercular alteration. Resolving, consolidation, scarring, calcification are considered good signs and reflect the stabilization of tuberculosis. In case of incomplete phase it is also recorded in the diagnosis as "incomplete resolving" or "incomplete consolidation".

Tb drug resistance is Tb resistance against one or more antimycobacterial agents. There are differentiated the following types of drug resistance:- primary drug resistance is found in new cases - in patients receiving antituberculous medication for not longer than 4 weeks or in cases with no previous history of antituberculous treatment. In Ukraine the frequency of the primary drug resistance is 23-25 % ;- secondary (acquired) drug resistance is found in patients receiving antituberculous medication for longer than 4 weeks; it is observed in 55-56 % of cases;- monoresistance is Tb resistance to one of five first line therapy drugs (isoniazid, streptomycin, rifampicin, ethambutol, pyrasinamide);- multiple drug resistance is Tb resistance to two or more antituberculous medications. Multiresistance is a type of multiple resistance against the combination of isoniazid and rifampicin or to these two combined with other medications. The testing of Tb susceptibility to antituberculous drugs is called culture and sensitivity test. Drug resistance causes: 1. Biological: insufficient medication concentration, individual pharmacokinetics (metabolic rate). 2. Patient-related: contacts with a patient with drug resistant tuberculosis, irregular or prematurely discontinued taking of medication, adverse reactions, inadequate treatment.3. Disease-related: treatment with one medication, low dose or short duration of treatment, prescription of drugs with cross-resistance. At Ihe alimentary mode of infection the possibility of primary infection depends on the condition of the bowels wall and bowels absorption. Plasmids can interact with chromosomes. Drug resistance genes are localized both on chromosomes and plasmids of Tb. Mycobacteria have DNA functioning as the main carrier of genetic information. The sequence of nucleotides in the DNA is called a gene. Genetic information of the DNA is not stable: it changes, evolves, and improves. Mycobacteria variability is their capability to gain new and/or regain old properties. One of Tb variability manifestations is their filtered and L-shaped forms. The filtered forms are minor Mycobacteria fragments

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appearing under unfavorable conditions and capable of reversion. The nature of these forms, their structure and role in tuberculosis pathogenesis are not well understood. L-shaped Tb was first described by Alexander Jackson in 1945. The cell wall in L-shaped Tb is either absent or defective. It is significant that bacterial cells morphology is altered and their metabolism is low. The cells have low virulence and are quickly destroyed in the environment. Because of the cell wall absence or defectiveness L-shaped Mycobacteria are stained with common dyes and so cannot be detected during bacterioscopy. Mycobacteria transform into L-shaped forms under treatment with antituberculous drugs and due to host's immunity. L-shaped Tb may survive in the host in stable and unstable state and are able to reverse into the original microbial state with virulence restoration. Stable L-shaped Tb are mostly contained in inactive tuberculosis foci.Слайд 28, 29 Etiologic verification of diagnosis is the basis for contemporary clinical phthisiology. There are only two reliable methods of tuberculosis verification: bacteriological and histological. The paragraph Verification Method should include the full range of respective data. For example, in case of Tb finding the diagnosis should read (TB+) followed by explanation:(M+) - positive swab bacterioscopy, meaning that acid-fast bacilli (AFB) were found in 2-3 sputum swabs during 3 consecutive days, stained after Ziehl-Neelsen;(M-) - negative swab bacterioscopy.Bacterioscopy is always completed with bacteriology, the culture of sputum on nutrient media of Levenstein-Yensen for 3 consecutive days. This information is reflected in the diagnosis as:(KO) - no culture performed;(K-) - negative culture for Tb;(K+) - positive culture for Tb.Thus, (TB+) is possible with (M-), but always with (K+).Each positive culture (K+) should include sensitivity testing for first line antibiotics like isoniazid (H), rifampicin (R), streptomycin (S), ethambutol (E), and pyrazinamide (Z). Sensitivity testing for second line antibiotics is performed along with testing for first line drug therapy to avoid repeated 1.5-2 month long culture in case of multiple and multi-resistant Tb. Drug resistance should be recorded as follows:(ResistO) - no testing performed for drug-resistant Tb;(Resist-) - first line therapy-resistant Tb not found;(Resist +) (R, H, S) - rifampicin, isoniazid, streptomycin-resistant Tb found.Drug resistance for second line antibiotics should be recorded as follows:(ResistIIO) - no testing performed for second line drug-resistant Tb;(Resist II-) - second line therapy resistance of Tb was not found;(Resist +) (K, Cf) - kanamycin and ciprofloxacin-resistant Tb found.In the absence of bacterioexcretion (TB-) culture results should be recorded as follows:(MO) - no swab taken;(M-) - the swab of 1-2 specimens out of 3 was negative;(KO) - no culture made;(K-) - Tb not found in the culture; culture for Tb is negative.Histological examination should be conducted with or without bacteriology and should be presented as follows:(HISTO) - no histology examination done;(HIST-) - tuberculosis is unconfirmed with histology;(HIST+) - tuberculosis is confirmed with histology.Слайд 30 Complications of tuberculosis.Complications are an addition to the basic diagnosis. Classification includes the most frequently observed complications. Tuberculosis complication is pathological processes related to tuberculosis proper or other diseases. For example, if tuberculosis is complicated with pulmonary hemorrhage, followed by middle lobe atelectasis resulting in pneumonia, then pulmonary hemorrhage is the complication of the 1 st degree, atelectasis - of the 2nd, and pneumonia - of the 3rd degree. Complications should be listed along with the data of their diagnosis.Complications of pulmonary tuberculosis: hemoptysis, pulmonary hemorrhage, spontaneous pneumothorax, pulmonary failure, cor pulmonale, atelectasis, amyloidosis, etc.

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Complications of extrapulmonary tuberculosis: bronchial stenosis, pleural empyema, fistula (bronchial, thoracic), kidney failure, adrenal crisis, infertility, adhesion, ankylosis, amyloidosis, rtc.Follow-up: clinical and dispensary categories of patients.After recording complications, if any, the physician should record the patient's category of treatment. There are the following categories and groups of tuberculous patients: 1 (Cat 1), 2 (Cat 2), 3 (Cat 3), 4 (Cat 4), 5 (Cat 5); group 5.1; group 5.2; group 5.3; group 5.4; group 5.5.When wording the diagnosis, one should also include the cipher of the cohort (1, 2, 3, 4) and note the year, to which the cohort belongs, e.g. Coh4 (2001), Cohl (2000), Coh3 (2002). With such a cohort cipher patients are followed up in dispensaries.Слайд 31. Treatment effectiveness. I. Effective treatment 1.1. Recovery. 1.2. Ceased bacterioexcretion. 2. Completed treatment. 3. Ineffective treatment (treatment failure). 4. Interrupted treatment. 5. Continuing treatment. 6. Transferred. 7. Lethal outcome. "Effective treatment" and "Completed treatment" are united in the category "Successful treatment". VII. Tuberculosis outcome.Tuberculosis outcome is residual changes after the clinical recovery from tuberculosis and postoperative changes related to tuberculosis. Residual changes are classified as great and small. A patient with residual changes is among those with the higher risk of tuberculosis relapse or a new disease. These residual changes are the signs of inactive tuberculosis. Residual changes after the clinical recovery from pulmonary tuberculosis: fibrotic, fibronodular, bullae and dystrophy, calcifications in the lungs and lymph nodes, pleuropneumosclerosis, cirrhosis, postoperative changes (followed by the record of the date and type of operation), etc. Residual changes after the clinical recovery from extrapulmonary tuberculosis: scarring in different organs and its outcome, calcifications, postoperative changes (followed by the record of the date and type of operation), etc. DIAGNOSIS CHANGE IN A TUBERCULOUS PATIENT FOLLOWING TREATMENT RESULTS As treatment progresses, diagnosis may change. For instance, culture results were positive after 1.5-2 months of treatment whereas at the beginning of treatment microscopy was negative. The clinical form and phase of tuberculosis may change, this can be recorded optionally. The change of disease phase can be done at any moment of treatment and depending on the patient's condition. Correction of the clinical form of the disease should be done right after its diagnosis. In cases of operative treatment and no residual changes in the lungs it is recommended to make the following record: "Postoperative state. Operated (date and type of operation) for such form of tuberculosis".