2. DR MUHAMMAD KHALID CHAUDHARY MBBS, MCPS, FCCP (USA), FCPS (PULMONOLOGY) ASSOCIATE PROFESSOR INSTITUTE OF CHEST MEDICINE KING EDWARD MEDICAL, UNIVERSITY / MAYO HOSPITAL, LAHORE

3. TUBERCULOSIS PROBLEM BASED LEARNING

4. CASE SCENARIO A 24 year old paper factory worker presented with 3 months history of COUGH, SPUTUM, HAEMOPTYSIS, FEVER, NIGHT SWEATS, LOSS OF WEIGHT and DECREASED APPETITE. He was a non smoker and belonged to poor socio- economic class. He was the youngest of the family of 6 sharing two rooms. His mother suffered from tuberculosis 2 years ago.

5. CASE SCENARIO- CLINICAL EXAMINATION On examination he looked underweight Pulse: 102/min Temperature: 99.6 F Respiratory Rate: 17/min Examination of the chest revealed dullness to percussion at the right upper chest and crackles on the same area on auscultation

6. DIFFERENTIAL DIAGNOSIS Pulmonary Tuberculosis (PTB) Pneumonia Bronchiectasis

7. CBC Hb: 11 g/dl TLC: Normal ESR: 45 mm 1 st hour

8. CHEST X-RAY

9. SPUTUM AFB smear + (ZN Stain)

10. SPUTUM AFB culture and sensitivity

11. DIAGNOSIS PULMONARY TUBERCULOSIS

12. FACTS ABOUT TUBERCULOSIS Most common cause of infectious disease related mortality world wide WHO estimates that two billion people have latent TB Three million deaths per year At least one person infected every second 80% of TB patients are in 15-54 year age group

13. GLOBAL Incidence – 136 /100,000 Smear positive – 60 /100,000 Prevalence – 206 /100,000 Mortality – 24 /100,000 PAKISTAN Ranks 5 th amongst 22 high burden countries Incidence – 231 (181) /100,000 (415800) Smear positive – 81 /100,000 Prevalence – 373 (329) /100,000 Mortality – 40 /100,000 BURDEN OF TB

14. History of TB

15. TB has affected humans for millennia Historically known by a variety of names, including: –Consumption –Wasting disease –White plague TB was a death sentence for many History of TB (1) Vintage image circa 1919 Image credit: National Library of Medicine

16. Until mid-1800s, many believed TB was hereditary 1865 Jean Antoine- Villemin proved TB was contagious 1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TB Mycobacterium tuberculosis Image credit: Janice Haney Carr History of TB (2) Scientific Discoveries in 1800s

17. Before TB antibiotics, many patients were sent to sanatoriums Patients followed a regimen of bed rest, open air, and sunshine TB patients who could not afford sanatoriums often died at home History of TB (3) Sanatoriums Sanatorium patients resting outside

18. Breakthrough in the Fight Against TB (1) Drugs that could kill TB bacteria were discovered in 1940s and 1950s Streptomycin (SM) discovered in 1943 Isoniazid (INH) and p-aminosalicylic acid (PAS) discovered between 1943 and 1952

19. Breakthrough in the Fight Against TB (2) TB death rates in U.S. began to drop dramatically Each year, fewer people got TB Most TB sanatoriums in U.S. had closed by mid 1970s

20. TB Resurgence Increase in TB in mid 1980s Contributing factors: –Inadequate funding for TB control programs –HIV epidemic –Increased immigration from countries where TB is common –Spread in homeless shelters and correctional facilities –Increase and spread of multidrug- resistant TB March 16, 1992 Newsweek Magazine Cover

21. Increased governmental funding for TB control programs beginning in 1992 Number of TB cases has steadily declined since 1993 Reported TB Cases, U.S., 1982-2008 TB Prevention and Control Efforts Year No. of Cases

22. 1840192018601900 1940196019802000 1880 1993: TB cases decline due to increased funding and enhanced TB control efforts 1993: TB cases decline due to increased funding and enhanced TB control efforts Mid-1970s: Most TB sanatoriums in U.S. closed 1884: First TB sanatorium established in U.S. 1865: Jean-Antoine Villemin proved TB is contagious 1943: Streptomycin (SM) a drug used to treat TB is discovered 1882: Robert Koch discovers M. tuberculosis Mid-1980s: Unexpected rise in TB cases 1943-1952: Two more drugs are discovered to treat TB: INH and PAS TB History Timeline

23. In what year was each of the following discoveries made? a.TB was proven to be contagious 1865 b.The bacterium that causes TB was discovered 1882 c.The first drug that could kill TB was discovered 1943 History of TB Study Question 1.1

24. TB Transmission

25. Transmission is defined as the spread of an organism, such as M. tuberculosis, from one person to another. TB Transmission (1)

26. M. tuberculosis causes most TB cases in Pakistan Mycobacteria that cause TB: –M. tuberculosis –M. bovis –M. africanum –M. microti –M. canetti Mycobacteria that do not cause TB –e.g., M. avium complex M. tuberculosis TB Transmission (2) Types of Mycobacteria

27. TB is spread person to person through the air via droplet nuclei M. tuberculosis may be expelled when an infectious person: –Coughs –Sneezes –Speaks –Sings Transmission occurs when another person inhales droplet nuclei TB Transmission (3)

28. TB Transmission (4) Dots in air represent droplet nuclei containing M. tuberculosis

29. Probability that TB will be transmitted depends on: –Infectiousness of person with TB disease –Environment in which exposure occurred –Length of exposure –Virulence (strength) of the tubercle bacilli The best way to stop transmission is to: –Isolate infectious persons –Provide effective treatment to infectious persons as soon as possible TB Transmission (5)

30. TB Transmission Study Question 1.2 What organism causes most TB disease in the Pakistan? M. tuberculosis What are 4 other mycobacteria that cause TB disease? M. bovis, M. africanum, M. microti, and M. canetti

31. TB Transmission Study Question 1.3 How is TB spread? TB is spread from person to person through the air via droplet nuclei containing M. tuberculosis.

32. The probability that TB will be transmitted depends on what four factors? Infectiousness of person with TB disease Environment in which exposure occurred Length of exposure Virulence (strength) of tubercle bacilli TB Transmission Study Question 1.4

33. Drug-Resistant TB

34. Caused by M. tuberculosis organisms resistant to at least one TB treatment drug –Isoniazid (INH, H) –Rifampin (RIF, R) –Pyrazinamide (PZA, Z) –Ethambutol (EMB, E) Resistant means drugs can no longer kill the bacteria Drug-Resistant TB (1)

35. Primary Resistance Caused by person-to-person transmission of drug-resistant organisms Secondary Resistance Develops during TB treatment: Patient was not given appropriate treatment regimen OR Patient did not follow treatment regimen as prescribed Drug-Resistant TB (2)

36. Mono-resistantResistant to any one TB treatment drug Poly-resistantResistant to at least any 2 TB drugs (but not both isoniazid and rifampin) Multidrug resistant (MDR TB) Resistant to at least isoniazid and rifampin, the 2 best first-line TB treatment drugs Extensively drug resistant (XDR TB) Resistant to isoniazid and rifampin, PLUS resistant to any fluoroquinolone AND at least 1 of the 3 injectable second-line drugs (e.g., amikacin, kanamycin, or capreomycin) Drug-Resistant TB (3)

37. Drug-resistant TB Study Question 1.5 What is drug-resistant TB? Drug-resistant TB is caused by M. tuberculosis organisms that are resistant to at least one TB treatment drug. Drug-resistant TB can be difficult to treat.

38. Drug-resistant TB Study Question 1.6 What is the difference between primary and secondary drug-resistant TB? Primary resistance is caused by person-to-person transmission of drug-resistant organisms. Secondary resistance develops during TB treatment. Either the patient was not treated with the right TB drugs or the patient did not follow the prescribed treatment regimen.

39. TB Pathogenesis

40. Pathogenesis is defined as how an infection or disease develops in the body. TB Pathogenesis (1)

41. Occurs when tubercle bacilli are in the body, but the immune system is keeping them under control Detected by the Mantoux tuberculin skin test (TST) or by blood tests such as interferon-gamma release assays (IGRAs) which include: –QuantiFERON ® -TB Gold test (QFT-G) –QuantiFERON ® -TB Gold In-Tube (QFT-GIT) –T-Spot ®.TB test (T-SPOT) People with LTBI are NOT infectious TB Pathogenesis (2) Latent TB Infection (LTBI)

42. Develops when immune system cannot keep tubercle bacilli under control –May develop very soon after infection or many years after infection About 10% of all people with normal immune systems who have LTBI will develop TB disease at some point in their lives People with TB disease are often infectious TB Pathogenesis (3) TB Disease

43. TB Pathogenesis (4) Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to small air sacs (alveoli)

44. TB Pathogenesis (5) Tubercle bacilli multiply in alveoli, where infection begins

45. TB Pathogenesis (6) A small number of tubercle bacilli enter bloodstream and spread throughout body

46. TB Pathogenesis (7) LTBI Within 2 to 8 weeks the immune system produces special immune cells called macrophages that surround the tubercle bacilli These cells form a barrier shell that keeps the bacilli contained and under control (LTBI)

47. TB Pathogenesis (8) TB Disease If the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and cause TB disease This process can occur in different places in the body

48. LTBI vs. TB Disease Latent TB Infection (LTBI) TB Disease (in the lungs) Inactive, contained tubercle bacilli in the body Active, multiplying tubercle bacilli in the body TST or blood test results usually positive Chest x-ray usually normalChest x-ray usually abnormal Sputum smears and cultures negative Sputum smears and cultures may be positive No symptomsSymptoms such as cough, fever, weight loss Not infectiousOften infectious before treatment Not a case of TBA case of TB

49. TB Pathogenesis Study Question 1.7 When a person inhales air that contains droplet nuclei containing M. tuberculosis, where do the droplet nuclei go? Most of the larger droplet nuclei become lodged in the upper respiratory tract, where infection is unlikely to develop However, droplet nuclei may reach the small air sacs of the lung (the alveoli), where infection begins

50. After the tubercle bacilli reach the small air sacs of the lung (the alveoli), what happens to them? Tubercle bacilli multiply in alveoli and some enter the bloodstream and spread throughout the body Bacilli may reach any part of the body Within 2 to 8 weeks, the immune system usually intervenes, halting multiplication and preventing further spread TB Pathogenesis Study Question 1.8

51. In people with LTBI (but not TB disease), how does the immune system keep the tubercle bacilli under control? The immune system produces special immune cells that surround the tubercle bacilli. These cells form a shell that keeps the bacilli contained and under control. TB Pathogenesis Study Question 1.9

52. TB Pathogenesis Study Question 1.10 How is LTBI detected? LTBI is detected by the Mantoux tuberculin skin test (TST) or blood tests such as interferon-gamma release assays (IGRA), which include the QuantiFERON ® -TB test (QFT-G), QuantiFERON ® -TB Gold In-tube (QFT-GIT), or T- SPOT.

53. What are the major similarities and differences between LTBI and TB disease? List characteristics of each. Latent TB Infection (LTBI) TB Disease (in the lungs) Inactive, contained tubercle bacilli in the body Active, multiplying tubercle bacilli in the body TST or blood test results usually positive Chest x-ray usually normalChest x-ray usually abnormal Sputum smears and cultures negativeSputum smears and cultures may be positive No symptomsSymptoms such as cough, fever, weight loss Not infectiousOften infectious before treatment Not a case of TBA case of TB TB Pathogenesis Study Question 1.11

54. TB Pathogenesis Study Question 1.12 What happens if the immune system cannot keep the tubercle bacilli under control and the bacilli begin to multiply rapidly? When this happens, TB disease develops. The risk that TB disease will develop is higher for some people than for others.

55. 55 TB Pathogenesis Sites of TB Disease

56. Sites of TB Disease (1) Bacilli may reach any part of the body, but common sites include:

57. Sites of TB Disease (2) LocationFrequency Pulmonary TB LungsMost TB cases are pulmonary Extrapulmonary TB Places other than lungs such as: Larynx Lymph nodes Pleura Brain Kidneys Bones and joints Found more often in: HIV-infected or other immunosuppressed persons Young children Miliary TB Carried to all parts of body, through bloodstream Uncommon

58. Sites for TB Study Question 1.16 What part of the body is the most common site for TB disease? Lungs are the most common site What are some other sites? - Larynx - Lymph nodes - Pleura (membrane around the lungs) - Brain - Kidneys - Bones and joints

59. Clinical Presentation SYMPTOMS Young people, < 54 years in more than 80% of cases Asymptomatic initially Tiredness, malaise, loss of appetite, weight loss, Low grade fever Cough > 3 Weeks Sputum mucoid, purulent, blood stained

60. Clinical Presentation SIGNS Emaciation Increased respiratory rate Dullness at affected area Crackles at affected area Tracheal deviation due to fibrosis

61. Diagnosis History Clinical Examination Sputum Examination - smear and culture Radiological Examination - CXR, CT. Routine Blood Tuberculin test PCR test Serological tests Special Circumstances – Gastric lavage &Throat swab in children – Bronchial lavage and transbronchial biopsy

62. Sputum Examination Ziehl- Nielson Staining (ZN staining) Fluorescence Staining Culture on L J Media – 3-8 weeks Culture on Bectic Media – 3-6 days

63. AFB - Ziehl-Nielson stain

64. 64

65. Colony Morphology – LJ Slant

66. Radiology X-Ray suggestive of TB Opacities in the upper zone Bilateral infiltrates Patchy or nodular shadow Presence of cavities Calcification Opacities that persist after few weeks

70. 70

75. Tuberculin testing Mantoux test: Intradermal inj. Of 0.1 ml (10 units) PPD Diameter of induration is measured in mm at 48-72 hours. < 6 mm NEGATIVE > 1O mm POSITIVE (past or present mycobacterial infection) If no BCG >15 mm POSITIVE if previous BCG

76. PPD Tuberculin Testing

77. PPD result after – 72 hours.

78. Tuberculin testing Heaf test Widely used in survey work A drop of undiluted tuberculin ( 100,000 IU/ ml) placed on skin, and 6 needle punctures are made through it with Heaf gun. Read after 3-7 days and graded as

79. Heaf test Grade 1: 4-6 small raised red dots Grade 2: Raised red ring with normal skin in middle Grade 3: Raised red circle Grade 4 : Raised red circle with blisters or ulcers Grade 2-4: Positive if no BCG Grade 3-4: Positive if previous BCG

80. PCR Theoretically capable of detecting a single organism in a specimen of sputum Todate its role in clinical practice is not clear Sensitivity 80%, specificity 89-97% (less than culture) Cost, delicate technique Serous cavity T.B

81. Basic principles of treatment Combination of antibiotics Combination of antibiotics – Rapid killing of mycobacteria Interruption of the chain of transmission Interruption of the chain of transmission – Prevention of drug resistance Long duration of treatment Long duration of treatment – Sterilisation of lesions Prevention of relapse Prevention of relapse

82. Drugs Available For Treatment of TB ESSENTIAL DRUGS - Isoniazid (H) - Rifampicin (R) - Pyrazinamide (Z) - Ethambutol (E) - Streptomycin (S)

83. Recommended Regimens New Cases. HRZE = 2 months intensive phase. HR = 4 months continuation phase. Re-treatment Cases. 5 Drugs regimen HRZES = initial 2 months. HRZE = upto 3 months. HRE = 5 months (continuation phase).

84. Module 1 – Transmission and Pathogenesis of Tuberculosis 84