Tuberculosis

1. Tuberculosis Bálint Beatrix MD, PhD SZTE, Dpt. of Pulmonology Deszk 2017. 11. 15

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

5. TB in EUROPE

6. Estimated WHO Regional TB statistics for 2011 Epidemiology

8. 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. 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 10 000 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.

11. WHO-approved microbiologic tests for tuberculosis Diagnosis of active TB 1.

12. WHO-approved microbiologic tests for tuberculosisDiagnosis of active TB 2.

13. The Xpert MTB/RIFis 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 itfor use in TB endemic countries and declared it a major milestone for global TB diagnosis.

14. 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.

15. 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

16. 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 neverget 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 mean10-year fatality rateof 70 % RECOVERY A full course of TBtreatment takes 6 to 9 months oftaking several drugs. Sources: CDC, PLoS One, WHO

17. 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.)

18. 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)

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

21. 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.

22. Tbc: tuberculoma

23. Tb pneumonia

24. Ghon komplex

25. Tb hilar adenopathy

26. Miliary tb

27. Tb: miliary

28. Tb: cavity

29. Tb: cavity

30. Tb: cavity

31. Tb:progressive

32. Callus pleurae, residuum

33. 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

36. Extrapulmonary tb

37. -*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

38. Laryngitis tuberculosa Constrictive Pericarditis. CT of chest: markedly thick pericardial calcification around the heart from patient with history of tb pericarditis

39. Resistant TB 1. Drugresistant tb: resistanttoone of theanti-TBdrugs. Multi-drug-resistanttuberculosis (MDR-TB):resistanttoatleastisonicid(INH) and rifampicin (RMP), the 2 most powerfulfirst-linetreatmentanti-TBdrugs. The reasons why multidrug resistance continues to emerge and spread are mismanagement of TB treatment and person-to-person transmission. -treatable TB whenthecourse of antibiotics is interrupted and thelevels of druginthe body areinsufficienttokill 100% of bacteria. (Patientsmayfeelbetter and halt theirantibioticcourse, drugsuppliesmayrun out orbecomescarce, patientsmayforgettotaketheirmedicationfromtimetotimeorpatientsdonotreceiveeffectivetherapy.) -MDR-TB is spreadfrompersontoperson.

40. Resistant TB 2. Extensivelydrugresistant 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 bothtakesubstantiallylongertotreatthanordinary (drug-susceptible) TB, and requiretheuse of second-lineanti-TBdrugs, whichare more expensive and have more side-effectsthanthefirst-linedrugsusedfordrug-susceptible TB.

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

42. 2007

43. 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.

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

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

46. 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.

47. The principles of therapy • Combination therapy (4-5) • kills more effectively • Shortens therapy • Prevents emergence of resistance: • INH/RAMP  EMB SM  PZA • Treatment must be for at least six month • Bactericidal phase: 1 month • Strerilizing phase: months 3 through 6 • Never add a single drug

48. 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

49. Daily therapy 6 months Daily treatment 180 doses 2-3 % relapse Short course 6 months Twice or three times weekly 52-114 doses Equivalent relapse Therapeutic Regimens

50. 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