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DR MUHAMMAD KHALID CHAUDHARY MBBS, MCPS, FCCP (USA), FCPS (PULMONOLOGY) ASSOCIATE PROFESSOR INSTITUTE OF CHEST MEDICINE KING EDWARD MEDICAL, UNIVERSITY / MAYO HOSPITAL, LAHORE TUBERCULOSIS PROBLEM BASED LEARNING 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 socioeconomic class. He was the youngest of the family of 6 sharing two rooms. His mother suffered from tuberculosis 2 years ago. 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 DIFFERENTIAL DIAGNOSIS Pulmonary Tuberculosis (PTB) Pneumonia Bronchiectasis CBC Hb: 11 g/dl TLC: Normal ESR: 45 mm 1st hour CHEST X-RAY SPUTUM AFB smear + (ZN Stain) SPUTUM AFB culture and sensitivity DIAGNOSIS PULMONARY TUBERCULOSIS 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 BURDEN OF TB GLOBAL PAKISTAN Smear positive – 60 /100,000 Ranks 5th amongst 22 high burden countries Incidence – 231 (181) /100,000 (415800) Smear positive – 81 /100,000 Prevalence – 206 /100,000 Prevalence – 373 (329) /100,000 Incidence – 136 /100,000 Mortality – 24 /100,000 Mortality – 40 /100,000 History of TB History of TB (1) • 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 Vintage image circa 1919 Image credit: National Library of Medicine History of TB (2) Scientific Discoveries in 1800s • Until mid-1800s, many believed TB was hereditary • 1865 Jean AntoineVillemin 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 (3) Sanatoriums • 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 Sanatorium patients resting outside 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 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 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 multidrugresistant TB March 16, 1992 Newsweek Magazine Cover TB Prevention and Control Efforts • Increased governmental funding for TB control programs beginning in 1992 • Number of TB cases has steadily declined since 1993 28,000 26,000 24,000 No. of Cases 22,000 20,000 18,000 16,000 14,000 12,000 10,000 1984 1987 1990 1993 Year 1996 1999 Reported TB Cases, U.S., 1982-2008 2002 2005 2008 TB History Timeline 1993: TB cases decline due to increased funding and enhanced TB control efforts 1865: Jean-Antoine Villemin proved TB is contagious 1840 1860 1884: First TB sanatorium established in U.S. 1880 1900 1882: Robert Koch discovers M. tuberculosis 1943: Streptomycin (SM) a drug used to treat TB is discovered Mid-1970s: Most TB sanatoriums in U.S. closed 1920 1960 1940 1943-1952: Two more drugs are discovered to treat TB: INH and PAS 1980 2000 Mid-1980s: Unexpected rise in TB cases History of TB Study Question 1.1 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 TB Transmission TB Transmission (1) Transmission is defined as the spread of an organism, such as M. tuberculosis, from one person to another. TB Transmission (2) Types of Mycobacteria • 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 (3) • 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 (4) Dots in air represent droplet nuclei containing M. tuberculosis TB Transmission (5) • 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 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 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. TB Transmission Study Question 1.4 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 Drug-Resistant TB Drug-Resistant TB (1) • 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 (2) 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 (3) Mono-resistant Resistant to any one TB treatment drug Poly-resistant Resistant 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 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. Drugresistant TB can be difficult to treat. 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. TB Pathogenesis TB Pathogenesis (1) Pathogenesis is defined as how an infection or disease develops in the body. TB Pathogenesis (2) Latent TB Infection (LTBI) • 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 (3) TB Disease • 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 (4) Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to small air sacs (alveoli) TB Pathogenesis (5) 2 bronchiole blood vessel tubercle bacilli alveoli Tubercle bacilli multiply in alveoli, where infection begins TB Pathogenesis (6) 3 brain bone lung kidney A small number of tubercle bacilli enter bloodstream and spread throughout body TB Pathogenesis (7) LTBI 4 special immune cells form a barrier shell (in this example, bacilli are in the lungs) • 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) TB Pathogenesis (8) TB Disease 5 shell breaks down and tubercle bacilli escape and multiply (in this example, TB disease develops in the lungs) • 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 LTBI vs. TB Disease Latent TB Infection (LTBI) TB Disease (in the lungs) Inactive, contained tubercle bacilli Active, multiplying tubercle bacilli in the body in the body TST or blood test results usually positive TST or blood test results usually positive Chest x-ray usually normal Chest x-ray usually abnormal Sputum smears and cultures negative Sputum smears and cultures may be positive No symptoms Symptoms such as cough, fever, weight loss Not infectious Often infectious before treatment Not a case of TB A case of TB 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 TB Pathogenesis Study Question 1.8 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 1.9 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 1.10 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 TSPOT. TB Pathogenesis Study Question 1.11 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 TST or blood test results usually positive Chest x-ray usually normal Chest x-ray usually abnormal Sputum smears and cultures negative Sputum smears and cultures may be positive No symptoms Symptoms such as cough, fever, weight loss Not infectious Often infectious before treatment Not a case of TB A case of TB 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. TB Pathogenesis Sites of TB Disease 55 Sites of TB Disease (1) Bacilli may reach any part of the body, but common sites include: Brain Larynx Bone Lymph node Pleura Lung Kidney Spine Sites of TB Disease (2) Location Pulmonary TB Lungs Extrapulmonary TB Places other than lungs such as: • Larynx • Lymph nodes • Pleura • Brain • Kidneys • Bones and joints Miliary TB Carried to all parts of body, through bloodstream Frequency Most TB cases are pulmonary Found more often in: • HIV-infected or other immunosuppressed persons • Young children Uncommon 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 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 Clinical Presentation SIGNS • Emaciation • Increased respiratory rate • Dullness at affected area • Crackles at affected area • Tracheal deviation due to fibrosis 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 Sputum Examination • • • • Ziehl- Nielson Staining (ZN staining) Fluorescence Staining Culture on L J Media – 3-8 weeks Culture on Bectic Media – 3-6 days AFB - Ziehl-Nielson stain 64 Colony Morphology – LJ Slant 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 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 PPD Tuberculin Testing PPD result after – 72 hours. 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 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 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 Basic principles of treatment • Combination of antibiotics –Rapid killing of mycobacteria •Interruption of the chain of transmission –Prevention of drug resistance • Long duration of treatment –Sterilisation of lesions •Prevention of relapse Drugs Available For Treatment of TB • ESSENTIAL DRUGS - Isoniazid (H) - Rifampicin (R) - Pyrazinamide (Z) - Ethambutol (E) - Streptomycin (S) 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). Module 1 – Transmission and Pathogenesis of Tuberculosis 84