1. Bálint Beatrix MD, PhD SZTE, Dpt. of Pulmonology Deszk
Tuberculosis
Bálint Beatrix MD, PhD
SZTE, Dpt. of Pulmonology
Deszk
2015.

2. Tuberculosis
TB a chronic bacterial infection, causes more deaths worldwide than any other infectious disease.
TB is spread through the air and usually infects the lungs, although other organs are sometimes involved.
Some 2 billion people - one-third of the world's population - are infected with the TB organism,
Tuberculosis kills 1.7 million people every year, and is the major killer of people living with HIV. Mycobacterium tuberculosis.

3. History 1. Paleopathological evidences - skeletal TB, bone TB
Ancient greek physisians used the word PHTYSIS
8th-9th century ¼ of the european adults died from TB.
Germ theory:
-Robert Koch (1882)-Pathogenicity of Mycobacterium tuberculosis
-Konrad Röntgen (1892)- X ray

4. TB in the World (number of TB cases)

5. TB in EUROPE

6. Epidemiology Region Incidence Prevalence Deaths Population Africa
Estimated WHO Regional TB statistics for 2011
Epidemiology
Region
Incidence
Prevalence
Deaths
Population
Africa
2,300,000
2,500,000
220,000
857,382,000
Americas
260,000
330,000
21,000
943,019,000
Eastern Mediterranean
660,000
1,000,000
99,000
608,628,000
Europe
380,000
500,000
45,000
899,500,000
South-East Asia
3,500,000
5,000,000
480,000
1,830,361,000
Western Pacific
1,700,000
130,000
1,808,797,000
Global Total
8,800,000
11,830,000
995,000
6,947,687,000

7. TB and HIV
People living with HIV are from times more likely to develop TB than persons without HIV.
TB is the most common presenting illness among people living with HIV, including among those taking antiretroviral treatment and it is the major cause of HIV-related death.
WHO policy on collaborative TB/HIV activities
Guidelines for national programmes and other stakeholders

9. Mycobacterium tuberculosis
The causative agents for tuberculosis
Discovered by Robert Koch in 1882
~25 % of world’s population infected
25 million is infected in USA

10. Mycobacterium tuberculosis: Tbc-t okozó baktérium Robert Koch 1882-ben fedezte fel

11. Microbiology
Mycobacterium tuberculosis: obligate, aerobic parazite, acid-fast
slow growth, visible colonial growth: 4-6 weeks
INH resistant and sensitive strains are different
Direct examination: Ziehl-Neelsen stain:
4 m long and 0,2-0,5 m wide
organism/ml of sputumsmear positive
Culture of sputum/fluid
M. tuberculosis: growths slowly, lack of pigment, produces Niacin: M. bovis: niacine negative
Drug sensitivity test.
Blood test: Today's policy recommendation applies to blood tests for active TB. Blood tests for inactive TB infection (also known as dormant or latent TB) are currently under review by WHO.
The new recommendation comes after 12 months of rigorous analysis of evidence by WHO and global experts. Overwhelming evidence showed that the blood tests produced an unacceptable level of wrong results - false-positives or false-negatives - relative to tests endorsed by WHO.

12. WHO-approved microbiologic tests for tuberculosis
Diagnosis of active TB 1.
Test
Site
Major Findings/results of Systematic review
Sputum smear
microscopy
Pulmonary
• fluorescence microscopy is on average 10% more sensitive than conventional microscopy. Specificity of both fluorescence and conventional microscopy is similar. Fluorescence microscopy is associated with improved time efficiency.
•Same-day sputum smear microscopy is as accurate as standard smear Microscopy. Compared with the standard approach of examination of two smears with light microscopy over 2 days, examination of 2 smears taken on the same day had much the same sensitivity (64% for standard microscopy vs 63% for same-day microscopy) and specificity (98% vs 98%)
nucleic acid amplification tests (NAATs) [other than Xpert MTB/RIF]
Pulmonary and extra-pulmonary TB
Commercial, standardized NAATs have high specificity and positive predictive value, however, they have relatively lower (and highly variable) sensitivity and negative predictive value for all forms of TB, especially in smear-negative and extrapulmonary disease

13. WHO-approved microbiologic tests for tuberculosis Diagnosis of active TB 2.
Site
Major Findings/results of Systematic review
Xpert MTB/RIF
Pulmonary TB and extrapulmonary
TB and RIF
resistance
Xpert MTB/RIF used as an initial diagnostic test for detection of M. tuberculosis and rifampicin is sensitive and specific. Xpert MTB/RIF is also valuable as an add-on test following microscopy for patients who are smear-negative.an Xpert MTB/RIF result that is positive for rifampicin resistance should be carefully interpreted and take into consideration the risk of MDR TB in a given patient and the expected prevalence of MDR TB in a given setting.
• when used as an initial test replacing smear microscopy Xpert MTB/RIF achieved a pooled sensitivity of 88% and pooled specificity of 98%.
• for detection of rifampicin resistance Xpert MTB/RIF achieved a pooled sensitivity of 94% and pooled specificity of 98%
Automated liquid
cultures and rapid
MPt64-based species
identification tests
Pulmonary TB and extrapulm.
TB specification
automated liquid cultures are more sensitive than solid cultures; time to detection is more rapid than solid cultures.
• mPT64-based rapid immunochromatographic tests (ICT) for species identification has high sensitivity and specificity

14. The Xpert MTB/RIF is an automated, cartridge-based nucleic amplification assay for the simultaneous detection of TB and rifampicin resistance directly from sputum in under two hours. It can identify Mycobacterium tuberculosis (MTB) DNA and resistance to rifampicin (RIF) by nucleic acid amplification technique (NAAT).
In 2010, the WHO endorsed it for use in TB endemic countries and declared it a major milestone for global TB diagnosis.
Atípusos Mycobacterium identifikálására is alkalmas.
Budapest OKTPI/ Corden Laboratóriumban elérhető

15. Mode of spread
TB is spread from in microscopic droplets person to person — droplet nuclei — expelled from the lungs when a TB sufferer coughs, sneezes, speaks, sings, or laughs. Only people with active disease are contagious.
People are most likely to be contagious when their sputum contains bacilli, when they cough frequently and when the extent of their lung disease, as revealed by a chest x-ray, is great.
* People who have been treated with appropriate drugs for at
least two weeks usually are not infectious.

16. Predisposing Factors Babies and young children HIV infection
substance abuse
diabetes mellitus
silicosis
cancer
leukemia or Hodgkin's disease
severe kidney disease
low body weight
certain medical treatments
corticosteroid treatment
organ transplants
chemotherapy

17. How Tuberculosis Affects The Body
COMMON SYMPTOMS
Fever
Coughing up blood or sputum
Weakness or fatigue
A bad cough that lasts
more than three weeks
TB is spread when you inhale the bacteria in droplets expelled then someone infected speaks or coughs.
Pain in the chest
No appetite
Weight loss

18. Sources: CDC, PLoS One, WHO
COURSE OF INFECTION
INFECTION
Can turn into either latent or active TB.
LATENT TB
In the initial stage of disease, called latent TB, TB bacteria remain alive, but cannot spread to other tissue or people. Most infections will never get past this stage. 10 % of latent TB infections become active.
ACTIVE TB DEATH
Active pulmonary TB Without treatment, (TB in the lungs) is contagious people who are HIV-negative have a mean 10-year fatality rate of 70 %
RECOVERY
A full course of TB treatment takes
6 to 9 months of taking several drugs.
Sources: CDC, PLoS One, WHO

19. HOW DOES TB DISEASE DEVELOP
HOW DOES TB DISEASE DEVELOP? There are two possible ways a person can become sick with TB disease:
1.A person who may have been infected with TB for years and has been perfectly healthy. The time may come when this person suffers a change in health. The cause may be another disease like AIDS or diabetes. Or it may be drug or alcohol abuse or a lack of health care because of homelessness. Whatever the cause, when the body's ability to protect itself is damaged, the TB infection can become TB disease. In this way, a person may become sick with TB disease months or even years after they first breathed in the TB germs.
2. A person first breathes in the TB germs the body is unable to protect itself against the disease. The germs then develop into active TB disease within weeks. (This way TB disease develops happens much more quickly.)

20. Symptoms Early TB (single or multiple nodule, caseous lesion)
- no symptomes
Progresszive TB (cavitation, pneumonitis)
- nonspecific symptomes: anorexia, fatigue, weight loss,
remittent fever,
night sweets
- cough, sputum (mucopurulent)
- haemoptysis
- chest pain (inflammation of parietal pleura)

21. Laboratory findings IIn advanced TB! RBC  Se albumin  WBC  Sodium 
Calcium 

22. Characteristic X-ray findings
Apical, subapical patchy infiltration
Bilateral upper lobe infiltration
Dissemination: miliary tb
Lower lobe TB
cavitation or infiltration
atelectesis, mass leasions, large cavitation with fluid, pneumonic-like infiltration
Non-specific
Pleural effusion
Special
Simon foci: The initial infection leaves nodular scars in the apices of one or both lungs, called which are the most common seeds for later active TB.
Ghon foci: calcified scars of primary infection and residual calcified hilar lymph nodes.

23. Tbc: tuberculoma

24. Tb pneumonia

25. Ghon komplex

26. Tb hilar adenopathy

27. Miliary tb

28. Tb: miliary

29. Tb: cavity

30. Tb: cavity

31. Tb: cavity

32. Tb:progressive

33. Callus pleurae, residuum

34. Diagnosis X-ray findings Sputum/bronchoscopic lavage fluid smear +
Negatíve tuberculin test: can not exclude the infection
Histology: TUBERCULOMA
epitheloid cells,
Langhans giant cells,
lymphocytes,
caseous lesion (necrosis)
Definitive diagnosis
- culture
- specification of the organism

35. Extrapulmonary TB (TB can involve any organ)
-TB of the tonsils, lymph nodes, abdominal organs, bones, and joints caused by ingestion of milk infected with M. bovis. (slaughtering cows with milk)
*GENITOURINARY TUBERCULOSIS
-kidney pyelonephritis. (chronic, "sterile" routine culture-negative)
-epididymis or prostate gland, baldder, vesicles.
-Salpingo-oophoritis
* TUBERCULOUS MENINGITIS (TB to the subarachnoid space)
* MILIARY TUBERCULOSIS (Generalized Hematogenous or Lymphohematogenous TB) Bone marrow involvement
* TUBERCULOUS PERITONITIS
*TUBERCULOUS PERICARDITIS
*TUBERCULOUS LYMPHADENITIS
*TUBERCULOSIS OF BONES AND JOINTS (Pott's disease)
*TUBERCULOSIS OF THE LIVER

36. Resistant TB 1.
Drug resistant tb: resistant to one of the anti-TB drugs.
Multi-drug-resistant tuberculosis (MDR-TB): resistant to at least isonicid(INH) and rifampicin (RMP), the 2 most powerful first-line treatment anti-TB drugs.
The reasons why multidrug resistance continues to emerge and spread are mismanagement of TB treatment and person-to-person transmission.
-treatable TB when the course of antibiotics is interrupted and the levels of drug in the body are insufficient to kill 100% of bacteria. (Patients may feel better and halt their antibiotic course, drug supplies may run out or become scarce, patients may forget to take their medication from time to time or patients do not receive effective therapy.)
-MDR-TB is spread from person to person.

37. Resistant TB 2.
Extensively drug resistant tb (XDR-TB). is defined as resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin, and kanamycin).
MDR-TB and XDR-TB both take substantially longer to treat than ordinary (drug-susceptible) TB, and require the use of second-line anti-TB drugs, which are more expensive and have more side-effects than the first-line drugs used for drug-susceptible TB.

38. In 2014, an estimated 480 000 people worldwide developed MDR-TB
In 2014, an estimated people worldwide developed MDR-TB. It is estimated that about 9.7% of these cases were XDR-TB.

39. Prevention of MDR TB
There are several ways that drug resistance to TB, and drug resistance in general, can be prevented:
Rapid diagnosis & treatment
Completion of treatment: Previous treatment of TB is an indicator of MDR TB. If the patient does not complete his/her antibiotic treatment, or if the physician does not prescribe the proper antibiotic regimen, resistance can develop. Also, drugs that are of poor quality or less in quantity, contribute to MDR TB.
Patients with HIV/AIDS should be identified and diagnosed as soon as possible. They have great risk of developing drug resistance.
Identify contacts who could have contracted TB: i.e. family members, people in close contact, etc.
Research: Much research and funding is needed in the diagnosis, prevention and treatment of TB and MDR TB.

40. History of chemotherapy
Streptomycin
Toxicity
Resistancy
Recidive infection
Isonicid
INH + PAS + Streptomycin
Treatment-18 months
Rifampicin 1970
RMP + INH 9 months
RMP + INH + ETB 6 months

41. Therapeutic agents for tb
First line therapy
Isoniazid
Rifampin
Pyrazinamide
Streptomycin
Ethambutol
Secund line therapy
Ethionamide
Cycloserine
Aminoglycosides
Capreomycin
PAS
Thiocetazone
Imipenem
Ampicillin
Metronidazole
Ciprofloxacin
Ofloxacin

42. Characteristics of 2nd line drugs
Less effective drugs
Poor GI tolarence
Significant side effect profile
Not well studied
Some not readily available (PAS)

43. Treatment
All patients who have not been treated previously and do not have other risk factors for drug resistance should receive a WHO-approved first-line treatment regimen using quality assured drugs. The initial phase should consist of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol.
The continuation phase should consist of isoniazid and rifampicin
given for 4 months. The doses of antituberculosis drugs used should conform to WHO recommendations. Fixed-dose combination drugs may provide a more convenient form of drug administration.

44. The principles of therapy
Combination therapy
kills more effectively
Shortens therapy
Prevents emergence of resistance:
INH/RAMP  EMB SM  PZA
Treatment must be for a least six month
Bactericidal phase: 1 month
Strerilizing phase: months 3 through 6
Never add a single drug

45. Initial therapy: four drugs
Isoniazid (INH) 300 mg daily
Rifampin (RIF) 600 mg daily
Pyrazinamide (PZA)25-30 mg daily
Ethambutol (EMB)25 mg initially

46. Therapeutic Regimens Daily therapy 6 months Daily treatment 180 doses
2-3 % relapse
Short course
6 months
Twice or three times weekly
doses
Equivalent relapse

47. Preventive therapy for tuberculous infection
Infection vs. active disease
Lifetime risk for active disease
Higher in children
10 % per year in HIV infected patients
Mantoux skin test is the indicator of infection
Preventive therapy requires 6 months of single drug therapy
Isoniazid

48. Therapy of MDR/XDR TB
Patients with or highly likely to have tuberculosis caused by drug-resistant (especially MDR/XDR) organisms should be treated with specialized regimens containing quality-assured second-line antituberculosis drugs.
The regimen chosen may be standardized or based on presumed or confirmed drug susceptibility patterns.
At least five drugs, pyrazinamide and four drugs to which the organisms are known or presumed to be susceptible, including an injectable agent, should be used in a 6–8 month intensive phase, and at least 3 drugs to which the organisms are known or presumed to be susceptible, should be used in the continuation phase.
Treatment should be given for at least 18–24 months beyond culture conversion.

49. TB and HIV 1.
People living with HIV are from times more likely to develop TB than persons without HIV.
TB is the most common presenting illness among people living with HIV, including among those taking antiretroviral treatment and it is the major cause of HIV-related death.
WHO-recommended collaborative TB/HIV activities
Tuberculosis Care with TB-HIV Co-management INTEGRATED MANAGEMENT OF ADOLESCENT AND ADULT ILLNESS (IMAI)

50. TB and HIV 2.
TB and HIV co-infection is when people have both HIV infection, and also either latent or active TB disease. When someone has both HIV and TB, each disease speeds up the progress of the other. In addition to HIV infection speeding up the progression from latent to active TB, TB bacteria also accelerate the progress of HIV infection.
In 2013 of the estimated 9 million people who developed TB an estimated 1.1 million (13%) were HIV positive. There were also in ,000 deaths from HIV associated TB equivalent to 25% of all TB deaths, and around 25% of the estimated 1.5 million deaths from HIV/AIDS.2
HIV infection and infection with TB bacteria are though completely different infections

51. Nontuberculous mycobacteria
Pumonary disease
M. avium, kansasii, abscessus, xenopi, malmoense
Lymphadenitis
M. avium, scrofulaceum, malmoense
Cutaneous disease
M. marinum, fortuitum, chelonea, ulcerans
Disseminated disease
M. avium, kansasii,chelonea, haemophilum

52. Treatment of nontuberculous mycobacteria
The antituberculotic drugs are usually not effective
M. kansasii: INH, RIF, EMB
M. avium: macrolide, Rifamycin, EMB
Rapid growers: clarithromycin and 2nd agents

53. History 2. Outstanding representatives of the arts and political life who suffered from TB
Balzac
Brontë sisters
Chekov
Chopin
Dostoevsky
Kafka
D.H. Lawrence
Sir Walter Scott
E. A. Poe
Voltaire
John Keats
Rembrandt’s wife (Sashka) and his son (Titus)
Marquise de Pompadur
Napoleon II

54. Literature
International standards For Tuberculosis Care 3rd edition,

55. Model: Simonetta Catanea died of TB at the age of 23.
Symptomes:whitish-pink colour of skin, small shoulders,
narrow thorax, low-placed and close breastssigns of phtisis