m. Moskovskovkiy prospekt Moskovskovkiy prospekt 197, Tuberculous

dispanser #7. You should go to the Clinic #2, then pass it by right side, then go straight to the Tuberculous

dispanser #7 (before the last building by left side) – 5-th floor building. Left stairs, 3-th floor, faculty

phthisiology and pulmonology.

http://Kfp.org.ua – to download the lectures

Lyashenko Alexandr Alexeevich

Phd, M.D. Lyashenko Alexandr Alexeevich

PhthisiologyPhthisiology

Lecture 1

• History of tuberculosis • Etiology, epidemiology, pathogenesis

of tuberculosis •TB transmission

• TB path morphology

DefinitionDefinition

«TB» – abbreviation of «tuberculosis»

«TB» – is “disease of poverty”

Tuberculosis (from Lat. tuberculum – node, + osis)- infectious disease caused by MBT. Science about tuberculosis is called Phthisiology (from Phthisis – dryness+ iatreia – treatment, Greek).

Tuberculosis is an ancient disease

The modern members of M. tuberculosis complex seem to have originated from a common progenitor about 15,000 - 35,000 years ago. TB was documented in Egypt, India, and China as early as 5,000, 3,300, and 2,300 years ago, respectively

Typical skeletal abnormalities, including Pott’s deformities, were found in Egyptian and Andean mummies

The disease was widespread in Egypt and Rome; it existed in America before Columbus , and in Borneo before any European contact

The White Plague

The TB epidemic in Europe, later known as the “Great White Plague”. By 1650, TB was the leading cause of mortality. Death rates increased rapidly, and by 1886, reached 9,000 per 100,000 people.

In the 18th century, TB was sometimes regarded as vampirism: red, swollen eyes, sensitivity to bright light, pale skin, and a blood-producing cough

In the 17th century. Franciscus Sylvius de la Böe of Amsterdam (1614-1672) was the first to identify the presence of actual tubercles as a consistent and characteristic change in the lungs and other areas of consumptive patients

The discovery of the tubercle bacillus

In Publication A New Theory of Consumptions, 1720, the English physician Benjamin Marten (1704-1722) was the first to conjecture that TB could be caused by “minute living creatures", which, once they had gained entry to the body, could generate the lesions and symptoms of phthisis

In 1865, the French military doctor Jean-Antoine Villemin (1827-1892) demonstrated that consumption could be passed from humans to cattle, and from cattle to rabbits

On the evening of March 24, 1882, in Berlin Robert Koch (1843-1910) made his famous presentation Die Aetiologie der Tuberculose. Using solid media made of potato and agar, Koch invented new methods of obtaining pure cultures of bacteria

History of TBHistory of TB

A further significant advance came in 1895, when Wilhelm Konrad von Röntgen (1845-1923) discovered X-rays. After this, the progress and severity of a patient's disease could be accurately documented and reviewed

Collapse therapy began around 1900, stimulated by the observation that spontaneous pneumothorax often led to healing

From 1908 until 1919, Albert Calmette (1863-1933) and Camille Guérin (1872-1961) in France serially passed a pathogenic strain of M. bovis 230 times, resulting in an attenuated strain called Bacille Calmette-Guérin or BCG

History of TBHistory of TB

Streptomycin was discovered by a doctoral student, Albert Schatz, working in the laboratory of Selman Waksman at Rutgers Agricultural College in New Jersey.

Jorgen Lehmann Working with the Swedish pharmaceutical company Ferrosan and its senior chemist, Karl-Gustav Rosdahl, the initial in vitro experiments with PAS began in December 1943

In 1951, three pharmaceutical companies — in the United States, Squibb and Hoffman La Roche, and in Germany, Bayer — almost simultaneously reported the effectiveness of isoniazid against tuberculosis

A variety of other drugs would also become available, but with the introduction of rifampin in the 1970s, a second bactericidal drug, and the subsequent development of both intermittent and short-course regimens of chemotherapy, the impression was again created that the battle against tuberculosis had been won

Disease names related to different clinical forms of TB

Phthisis Original Greek name for TB

Lung Sickness TB

Consumption TB

Lupus vulgaris TB of the skin

Mesenteric disease TB of the abdominal lymph nodes

Pott’s disease TB of the spine

Scrofula TB of the neck lymph nodes

King´s evil TB of the neck lymph nodes

White Plague TB especially of the lungs

White swelling TB of the bones

Milliary TB Disseminated TB

EpidemiologyEpidemiology

Infection rate is percentage of positive tuberculin skin test cases divided by the total number of examined, excluding persons with post-vaccination immunity. Infection rate is determined by Mantoux test with 2 international units (IU) of international standard of purified protein derivative (PPD-L). According to Y.I.Feshenko (2002) due to epidemics of tuberculosis in Ukraine, infection is 8.5% in children of 7-8 years, 19.5% in children aged from 13-14 years, and 80-90% in adults before 40 years.

Incidence rate is number of new cases with clinically active disease per 100,000 population at specific region in a given year.

EpidemiologyEpidemiology

Morbidity is number of old and new cases with clinically active disease per 100,000 population at specific region in a given year.

Mortality is number of deaths assigned to tuberculosis during a given year as expressed per 100,000 population of given region.

EpidemiologyEpidemiology

one person out of three is infected with Mycobacterium tuberculosis – two billion people in total

About 8 millions new TB cases in the world and about 2 millions death are registered .

Every 15-20 seconds, someone in the world dies from TB

Ninety-five per cent of all cases and 99 % of deaths occur in developing countries

TB is predominantly a disease of adults. Although children of 0–14 years make up 30 per cent of the world’s population, they account for only 10 per cent of TB cases

EpidemiologyEpidemiology

Where transmission rates are high, such as in Peru, Haiti and Bolivia, TB incidence peaks in young adults

EpidemiologyEpidemiology

As transmission falls, the average age of TB cases increases; in industrialized countries where transmission rates are now low, the majority of indigenous TB cases are found among the elderly

EpidemiologyEpidemiology

According to WHO all countries of Europe have been assigned into three groups of incidence rate of tuberculosis:

countries with low incidence rate (less then 10 cases per 100,000 population) are Austria, Germany, Greece, Norway, France, Switzerland, Sweden, Czech Republic and other countries.

countries with medium incidence rate (between 10 and 30 cases per 100,000 population). These are Bulgaria, Hungary, Poland, Turkey, Spain and Portugal.

countries with high incidence rate (over 30 cases per 100,000 population). All of countries of former Soviet Union and Romania belong to this group.

EpidemiologyEpidemiology

Among new cases 17% were workers, 3.6% were farmers, 4.3% were employees, with almost half of them were medical personnel (2%, or 850), 4.1% of students, 40% of total number were of able-bodied age who did not work, 15.3% -pensioners, 3.5% were once recently released from prison, 1.9% were homeless.

EpidemiologyEpidemiology

Risk factors of TB

The list of known risk factors for TB is long and growing.- HIV co-infection - Other factors known to enhance the risk of TB include

diabetes, silicosis, malnutrition (with or without HIV infection), and the smoke from domestic stoves and cigarettes.

Microbiology of Tuberculosis

Causative agent of tuberculosis belongs to Mycobactrium species, order of Actinomycetales, class of Schisomycetes.

Representatives of Mycobacterium species also cause leprosy, many of them are saprophytes found in smegma, cerumen, sputum from bronchiectases. They are also acid fast microbes vegetating on mucosal surface, on butter, on milk, on plants, in water, in soil etc.

Microbiology of TuberculosisSpecies Principal hosts Humans as secondary hosts

M. tuberculosis Humans –

M. bovis Cattle, deer, elk, bison, badger, opossum

Yes

M. caprae Goats Yes

M. africanum Humans -

M. microti Vole, hyrax, llama Very rare

‘M. canettii’ Humans –

M. pinnipedii Seal Very rare

Table 4.2 Members of the Mycobacterium tuberculosis

Atypical Mycobacterium Species

Group I (photochromogens) produce lemon-yellow pigment on exposure to light; takes 2-3 weeks for a colony to grow. Representatives are M.kansasii, M.marinum.

Group II (scotochromogens) produce yellow-orange pigments in the dark or on exposure to light. Representatives are M. aquae, M.scrofulaceum.

Group III (nonphotochromogens) produce weak or no pigment; it takes 5-10 days for a colony to grow. Representatives are M. avium, M.intracellulare, M.xenopi, M.haemophilum.

Group IV (rapid growers) forms colony in 2-5 days. These are predominantly saprophytes (M.phlei, M.smegmatis, M.fortuitum).

Atypical Mycobacterium Species

Group I (photochromogens) produce lemon-yellow pigment on exposure to light; takes 2-3 weeks for a colony to grow. Representatives are M.kansasii, M.marinum.

Group II (scotochromogens) produce yellow-orange pigments in the dark or on exposure to light. Representatives are M. aquae, M.scrofulaceum.

Group III (nonphotochromogens) produce weak or no pigment; it takes 5-10 days for a colony to grow. Representatives are M. avium, M.intracellulare, M.xenopi, M.haemophilum.

Group IV (rapid growers) forms colony in 2-5 days. These are predominantly saprophytes (M.phlei, M.smegmatis, M.fortuitum).

mycobacteriosis

Their causative role is considered proven when these are cultured from patient’ material twice and when they form multiple colonies at the absence of other causative agents

The pathogenesis of TB

Initial infection with the tuberculous bacilli occurs by the airborne route

Since Mycobacterium tuberculosis contains no enzymes that allow it to penetrate mucus, the organisms must be in a particle small enough (<5 /µm) to penetrate to the alveolar zone, where no mucus is present

While for humans the minimal infecting dose of M. tuberculosis is unknown

pathogenesis of TB

These initial organisms will be ingested by alveolar macrophages. Since resident alveolar macrophages and nonactivated, recently arrived monocytes cannot kill intracellular M. tuberculosis, the organisms replicate within macrophages and rapidly increase in number. It is during this period, before the development of specific immunity, that the organisms will appear in draining lymph nodes. Subsequently, a bacteremia or hematogenous dissemination will occur

pathogenesis of TB

After several weeks of uninhibited growth of M. tuberculosis, an immune response develops (see below) that results in a cessation of bacillary growth. At the site of initial infection (primary infection), the organisms may be completely eliminated. However, at the sites of bacillary spread through hematogenous dissemination, the organisms may persist but with arrested growth

VIRULENCE FACTORS Three constituents of the outer layers of the complex cell

walls of M. tuberculosis— cord factor, sulfolipids, and mycosides —have been considered virulence factors, although the supportive evidence is less than clearcut. Cord factor, now known to be trehalose dimycolate, has toxic activities

Sulfolipids are found in virulent strains of M. tuberculosis and enhance the toxicity of cord factor

Species-specific surface mycosides (glycoli- pids and glycopeptidolipids) constitute an electron-transparent zone around intracellular organisms, conferring protection against the hostile intracellular environment.

VIRULENCE FACTORS

Lipoarabinomannan (LAM) is a major cell wall polysaccharide constituent that may act as a virulence factor by a number of documented interactions with the host immune system. LAM from virulent M. tuberculosis differs from LAM from nonpathogenic mycobacteria in its enhanced capacity to stimulate production of tumor necrosis factor alpha (TNFa) by mononuclear phagocytes.

Mycobacterium tuberculosisMycobacterium tuberculosiscomplex complex

M. tuberculosis M. BovisM. africanumM. MicrotiBCG (Bacille Calmette-Guerin)M. CanettiiM. CapraeM. pinnipedii

History of tuberculosisHistory of tuberculosis

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