l Lecture 1 Determination of tuberculosis as a

l Lecture 1 Determination of tuberculosis as a scientific and practical problem. l History of development of phthisiology. Epidemiology of tuberculosis. Description of exciter. Pathogenic of tuberculosis. l Diagnoctics of tuberculosis l l Prof. L. A. Hryshchuk

The World Health Organization (WHO) proclaimed tuberculosis to be the global danger. According to its forecasts there will be 90 million new tuberulosis cases in the world during the decade. Of those who will fall ill approximately 30 million people may die in the current decade unless the reaction to this global problem radically improves. Nowadays the world scientists distinguish threeunion tuberculosis epidemic: the first is the epidemic of typical tuberculosis that is treated well; the second is the epidemic of chemioresistant tuberculosis and the third one is the epidemic of tuberculosis and the AIDS.

Rate per 100. 000 population/year Incidence TB/HIV incidence Rate per 100. 000 population/year Europe, 1990 -2010 Rate per 100. 000 population/year TB/HIV incidence, Prevalence MDG target for prevalence Mortality MDG target for mortality Source: Global TB control report, 2011 3

l The incidence of TB has slowly declined during the past years, reaching 48 (confidence intervals 44 -50) per 100 000 population in 2009. l However there is a big discrepancy between east and west. l The TB prevalence decreased from 96 (confidence intervals 70 -130) to 63 (confidence intervals 49 -81) per 100 000 population between 1990 and 2009 against a target of below the prevalence of 48 set out in the target for 2015. l Mortality from TB must further decline, from 6. 9 (confidence intervals 5. 7 -8. 3) per 100 000 persons in 2009 to 6 by 2015.

TB incidence

TB/HIV incidence, 2010 6

We will start with the patient since they are typically the source of infection. This slide shows a violent sneeze caught on film by high speed photography showing large liquid droplets. Most of these large, visible droplets will fall to the ground. However, the small droplet nuclei that can reach the deep lung are

According to the WHO criteria from 1995 tuberculosis epidemic has been registered in Ukraine in so far as tuberculosis patients comprise over 1 % of the total number of the population. The statistics of sickness in all the forms of tuberculosis in 2009 was 72, 7 persons per 100 thousand of the population. Alarming is the fact that tuberculosis “has turned younger”, its number among children, able-bodied and reproductive ages increases.

HISTORICAL REVIEW Tuberculosis, as an illness, is known since ancient times. Tuberculosis (TB) is believed to have been present in humans for thousands of years. Skeletal remains show that prehistoric humans (4000 BC) had tuberculosis, and tubercular decay has been found in the spines of Egyptian mummies (3000 -2400 BC).

The term “phthisis”, consumption, appears first in Greek literature. Around 460 BCE, Hippocrates identified phthisis as the most widespread disease of the times, and noted that it was almost always fatal. l Due to common phthisis-related fatalities, he wrote something no doctor would dare write today: he warned his colleagues against visiting TB patients in late stages of the disease, because their inevitable deaths might damage the reputations of the attending physicians. l

The study of tuberculosis, sometimes known as phthisiatry, dates back to ''The Canon of Medicine'' written by Ibn Sina (Avicenna) in the 1020 s. He was the first physician to identify pulmonary tuberculosis as a contagious disease, the first to recognise the association with diabetes, and the first to suggest that it could spread through contact with soil and water.

The fact that tuberculosis is infectious was confirmed by Fracastoro in the 16 th century.

It was Morton who published the first monograph “Phthisiology or a treatise on the phthisis” ( R. Morton, 1689) and named a science of tuberculosis “phthisiology” (from the Greek word “phthisis” ). In the 17 th 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 19 th 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 Fig. 1. R. Koch (1843 -1910)

M. I. Pyrohov studied clinico-morphological properties of tuberculosis of various localization and for the first time described typhoid form of miliar tuberculosis, histologic structure of tuberculous granuloma.

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.

An important achievement of the start of the 20 th 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.

THE WORLD TUBERCULOSIS EPIDEMIOLOGICAL SITUATION More than 2 billion people (about one-third of the world population) are estimated to be infected with tuberculosis. The global incidence of TB peaked around 2003 and now appears to be declining slowly. In 2006 the World Health Organization (WHO) issued the following estimates : The prevalence of active infection was 14. 4 million, corresponding to a prevalence rate of 219/100, 000 persons. The incidence of new cases was estimated to be 9. 2 million, corresponding to an incidence rate of 139/100, 000. Twelve of the 15 countries with the highest estimated TB incidence are in Africa, where the TB incidence rate was 363/100, 000 . In 2006 there were 1. 7 million deaths from TB worldwide, a death rate of 25/100, 000.

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 for the 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 2009 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 Kirgistan (127, 8), Kazakhstan (126, 4), Georgia (124, 4), Turkmenistan (86, 1 per 100. 000 of the population) (fig. 3).

Morbility on tuberculosis and HIV in Ukraine The statistics of morbidity in all forms of tuberculosis in Ukraine from 1990 to 2011 increased from 32 to 68, 4 per 100 thousand population/

The pathogenesis of tuberculosis. Infection with Mycobacterium tuberculosis, the causative agent, follows a relatively well-defined sequence of events. The infectious bacilli are inhaled as droplets from the atmosphere. In the lung, the bacteria are phagocytosed by alveolar macrophages and induce a localized proinflammatory response that leads to recruitment of mononuclear cells from neighbouring blood vessels. These cells are the building blocks for the granuloma, or tubercle, that defines the disease.

The granuloma consists of a kernel of infected macrophages, surrounded by FOAMY GIANT CELLS and macrophages with a mantle of LYMPHOCYTES delineating the periphery of the structure. l This tissue response typifies the 'containment' phase of the infection, during which there are no overt signs of disease and the host does not transmit the infection to others. Containment fails after a change in the immune status of the host, which is usually a consequence of old age, malnutrition, or HIV-co-infection. l Under such circumstances, the centre of the granuloma undergoes caseation and spills viable, infectious bacilli into the airways. This leads to development of a productive cough that facilitates aerosol spread of infectious bacilli. l

Pathogenesis of Tuberculosis

Etiology M. tuberculosis M. bovis M. africanum

Thin section transmission electron micrograph of Mycobacterium tuberculosis

The granuloma consists of a kernel of infected macrophages, surrounded by FOAMY GIANT CELLS and macrophages with a mantle of LYMPHOCYTES delineating the periphery of the structure

Automated screening molecular genetic test to identify Mycobacterium tuberculosis and resistance R - Xpert MBT / Rif

l l Cultures were on a liquid environment: automated microbiological analyzer BACTEC MGIT 960 Performed in all patients with pulmonary tuberculosis (with positive and negative sputum smear) Test drug sensitivity to drugs and second row Growth of Mycobacterium tuberculosis in 7 -14 days. Increases confirm TB in patients with negative sputum smear at 20%

At a molecular genetic test: Geno. Type MTBDRplus Perform all patients with Positive sputum smear Carried out in parallel with the classical culture method Detects DNK MBT , resistance to isoniazid and rifampin and isoniazid combination

Planting on solid medium Performed in all TB patients lungs (with positive and negative smear sputum): Bank of cultures Test drug sensitivity drugs II series

CLINICAL CLASSIFICATION OF TUBERCULOSIS l I. TYPE OF TUBERCULOUS PROCESS l 1. First diagnosed tuberculosis – FDTB (date of its ascertainment) l 2. Tuberculosis relapse – TBR (date of its ascertainment) l 3. Chronic tuberculosis – CTB (date of its ascertainment)

l l l l l II. CLINICAL FORMS OF TUBERCULOSIS A 15. -A 16. – Lung tuberculosis (LTB) (from a facultative designation of the form of injury) A 15. -16. - Primary tuberculous complex A 19. - part Disseminated lung tuberculosis A 15 -16. Nidus lung tuberculosis A 15 -16. Infiltrative lung tuberculosis A 15 -16. - Caseous pneumonia A 15 -16. - Lung tuberculoma A 15 -16. Lung fibrous-cavernous tuberculosis A 15 -16. - Lung cirrhotic tuberculosis A 15 -16. /J 65 Tuberculosis of respiratory organs combined with dust professional lung diseases (coniotuberculosis)

III. CHARACTERISTIC OF TUBERCULOUS PROCESS l 1. Localization of defect l l l Localization of defect in lungs according to the numbers (names) of segments, names of lung sections, and in other organs and systems – according to anatomical names of localization of a failure. 2. Presence of destruction (Destr +) destruction is present (Destr -) destruction is not present facultatively it is necessary to specify a phase of tubercular process: infiltration, decay (Destr +), sowing; suction, condensation, scarring, calcination.

3. Etiologic confirmation of tuberculosis diagnosis l l l l l (MBT +) it is confirmed by the results of bacteriological analysis (code A 15), in this case to specify: (M +) positive result of sputum analysis on acid-resisting bacteria (ARB); (C 0) cultural analysis was not done; (C -) negative result of cultural analyses; (C +) positive result of cultural analyses, in that case to specify: (Resist 0) MBT resistance to preparations of I line was not analysed; (Resist -) resistance to preparations of I line has not been established; (Resist +) ( abbreviation of antitubercular preparations of I line) resistance МBТ to preparations of I line has been established (in brackets to list all the preparations of I line to which resistance has been determined). (Resist II 0) MBT resistance to preparations of II line was not analysed; (Resist II-) resistance to preparations of II line has not been established; (Resist II+) ( abbreviation of antitubercular preparations of II line) resistance МBТ to preparations of I line has been established (in brackets to list all the preparations of I line to which resistance has been determined). ( МBТ-) is not confirmed by the results of bacteriological analysis (the code A 16), in this case to specify: (S 0) sputum was not investigated; (S -) negative result of sputum analysis on acid-resisting bacteria (ARB); (C 0) cultural analysis was not done; (C- ) negative result of cultural analysis; (Hist 0) histologic analysis was not carried out; (Hist -) is not confirmed by the results of histologic analysis (the code A 16); (Hist +) it is confirmed by the results of histologic analysis (the code A 15).

IV. COMPLICATIONS OF TUBERCULOSIS l Complications of lung tuberculosis (LTB): haemoptysis, lung haemorrhage, spontaneous pneumothorax, lung insufficiency, chronic lung heart, atelectasis, amyloid disease etc. l Complications of extrapulmonary tuberculosis (Ep. TB): bronchus stenosis, pleura empiema, fistulae (bronchial, thoracic), renal (adrenal) insufficiency, sterility, commissure, ankylosis, amyloid disease etc.

V. CLINICAL AND DISPENSARY CATEGORY OF THE REGISTRATION PATIENT Category 1 (Cat 1) First diagnosed tuberculosis with bacterial excretion (FDTB МBТ +), and also other grave and wide-spread forms of the disease without bacterial excretion (FDTB МBТ-) l Category 2 (Cat 2) Relapses of tuberculosis (RТB МBТ +) and (RТB МBТ-) and first diagnosed tuberculosis inefficiently treated ( FDTB IT МBТ +) and (FDTB IT МBТ-) l Category 3 (Cat 3) First diagnosed tuberculosis with the limited process, without bacterial excretion (FDTB МBТ-) and tuberculosis of unstated localization in children (tubintoxication) l

l l l l Category 4 (Cat 4) Chronic tuberculosis (CТ) of various localizations МBТ + and МBТCategory 5 (Cat 5) Risk groups to tuberculosis or its reactivation Group 5. 1 residual changes of cured tuberculosis, Group 5. 2 contact persons, Group 5. 3 adults, tuberculosis patients of doubtful localization, Group 5. 4 children and teenagers with latent tubinfection, persons from risk group, and also children who were not vaccinated in the neonative period and with postvaccinal complications. Group 5. 5 children and teenagers whose etiology of sensitivity to tuberculin it is necessary to specify, or character of changes in the lungs with the purpose of difdiagnosis.

VII. TUBERCULOSIS CONSEQUENCES Residual changes after healed lung tuberculosis: fibrous, fibrous-nidus, bullous-dystrophic, calcinates in lungs and lymphatic nodes, pleuropneumosclerosis, cirrhosis, consequences of surgical intervention (with the indication of the type and the date of an operation), etc. l Residual changes after healed tuberculosis of extrapulmonary localisation: cicatricial changes in various organs and their consequences, calcinosis, consequences of surgical intervention (with the indication of the type and the date of an operation). l

ORGANIZATION OF ANTITUBERCULOUS ACTIVITY IN THE PERIOD OF TUBERCULOSIS EPIDEMY Tuberculosis is a social disease and is a mirror of social-economic prosperity of the state and the well-being of its people, therefore antituberculous measures under present conditions must be taken on the national level by the government of the country. l At present time, the principal task in fighting tuberculosis in Ukraine is to take the epidemy of the illness under control (I stage), to stabilize the epidemiological indices (infestation, morbidity, sickliness and death rate) of tuberculosis (2 stage), and then their gradual decrease (3 stage). l For the successful organization of antituberculous measures close cooperation of the medical system, sanitary-epidemiological service and the organs of the state power is necessary. The general organization and methodological guidance of antituberculosis activity in this country is realized by the Ministry of Health Protection of Ukraine and Acad. F. G. Yanovsky Ukrainian phthisiology and pulmonology research institute (scheme 1). l

STRUCTURE OF ANTITUBERCULOSIS SERVICE IN UKRAINIAN l l l l The Ministry of Health Protection Acad. F. G. Yanovsky Ukrainian phthisiology and pulmonology research institute Regional of antituberculous dispensary Distric(town) of antituberculous dispensaries Tubcabinet At child’s policlinic At medical parts

l l l Antituberculous dispensary (Engl. dispensation – distribution) is a specialized medicative-prophylactic institution, which work is aimed at lowering morbidity, sikliness, infestation with tuberculosis and death rate caused by it as well as at conducting a complex of organizational and methodical, prophylactic antituberculous measures among the district population. The main tasks of an antituberculous dispensary are: 1) prophylaxis; 2) early revealing; 3) treatment of tuberculosis patients; 4) registration of groups of tuberculosis patients and contingents of persons

l Other very important tasks of an antituberculous dispensary are revealing, registration and treating tuberculosis patients. The results of treating tuberculosis patients to a considerable degree depend on the disease being timely revealed. In this connection, firsty diagnozed tuberculosis patients are divided into three groups: timely, untimely and lately revealed. For children and teenagers the fourth group is separated – early revealing. l The main criteria of dividing patients into groups are the character of a specific process, the presence or absence of destruction (cavern) and bacterial excretion, peculiarities of the prognosis at treatment, the degree of a patient’s danger for healthy persons.

l Children and teenagers, in whom the following factors are diagnosed, compose a group of early revealed: l 1) tuberculin test range; l 2) primary tubinfestation; l 3) hyperergic Mantoux test; l 4) tuberculous intoxication.

DISPENSARY CATEGORY Contingents of antitubercular dispensaries are divided into categories, which enables to examine them differentially, define the treatment tactics, perform prophylactic and rehabilitation actions. l Contingents of adult persons, children and teenagers due to being observed at an antitubercular dispensary, are divided into 5 dispensary categories: 1, 2, 3, 4 and 5. l To 5 categories (Cat 5) are referred dispensary contingents of risk to disease to a tuberculosis and its relapse. l