LRTI-Part 5 Tuberculosis

1. LRTI-Part 5Tuberculosis Chitra Pai, MD Liisa Russell, MD Athena Lin, PhD

2. Tuberculosis-Introduction • A chronic progressive disease associated with very high morbidity and mortality. • A potentially serious disease that mainly affects the lungs but can disseminate to different parts of the body. • One of the world’s top infectious killers • Caused by the acid fast bacteria-Mycobacterium tuberculosis. • TB is the leading cause of death among people with AIDS • Multi-drug resistant strains of TB-greatest challenge for effective treatment.

3. Epidemiology • More than 1.7 billion people (about 25 percent of the world population) are estimated to be infected with M. tuberculosis. • Worldwide, in 2017, 10 million individuals became ill with TB and 1.6 million died. • Highest rates are seen in sub-Saharan Africa, India, and the islands of Southeast Asia and Micronesia.  • No country has ever eliminated TB. • An estimated 490,000 people were infected with MDR-TB • 95% of TB deaths occurred in low- and middle-income countries.

4. TB statistics in the US • In 2017, a total of 9,105 TB cases were reported in the United States. • This represents a 1.6% decrease from 2016. Eleven states, the District of Columbia (DC), and New York City reported incidence rates above the national average of 2.8 cases per 100,000. Key finding (CDC) The rate of decline in the United States remains too slow to achieve TB elimination in this century. • More than 2,000 people are diagnosed with TB disease in CA each year (20-30 in Solano County) • 2.4 million in CA are living with TB infection

5. Epidemiology-High risk groups • HIV (+) / Immunocompromised patients • Close contacts of a person with infectious TB disease • Persons who have immigrated from areas of the world with high rates of TB • Children less than 5 years of age who have a positive TB test • Homeless persons • Injection drug users • Persons who work or reside with people who are at high risk for TB in facilities or institutions such as hospitals, homeless shelters, nursing homes and residential homes for those with HIV

6. Presentations of TB • Latent TB Infection (LTBI) TB disease • Symptomatic • May be infectious and contagious • Tuberculin test mostly positive • Chest X-ray findings-may be abnormal • Sputum smear for AFB may be positive • Curable with multiple antibiotics • Asymptomatic • Non infectious • Usually have a positive Tuberculin test • Chest X ray findings- normal • Sputum smears-negative • May develop TB disease if they do not receive treatment for latent TB infection

7. TB-disease presentation • Symptoms will depend on the body-site of involvement. Pulmonary TB -most common. Classical symptoms: Fever with sweating at night Chronic cough, productive cough and hemoptysis Chest pain Others- Weight loss, weakness, loss of appetite Extra-pulmonary TB TB disease in any part of the body other than the lungs (for example, the kidney, spine, bones, brain, or lymph nodes).

8. REACTIVATION/ SECONDARY TB Clinical features PRIMARY TB May be asymptomatic/ symptomatic Fever , malaise, cough Chest Radiographs: infiltrates in the mid-zones of the lung and enlarged draining lymph nodes in the area around the hilum. Features of disseminated TB (if it occurs) • Cough ( productive) • Fever, malaise, fatigue • Night sweats and weight loss • Chest Radiograph: infiltrates in the apices of the lung coalesce to form cavities with progressive destruction of lung tissue. • Extra-pulmonary TB: Kidneys, bones, Brain and meninges, bowel

9. Etiology and Transmission of TB Reservoirs • Human host-for Mycobacterium tuberculosis Active and open cases of TB transmit infection • Infected cows/ livestock- for Mycobacterium bovis Modes of infection- • Inhalation of droplet nuclei/ aerosols • Ingestion of raw milk from infected animals • Acid fast bacilli- • Mycobacterium tuberculosis • Mycobacterium bovis

10. M.tuberculosis- characteristics • Acid-fast bacteria ( due to mycolic acid) • Rod-shaped • Obligate aerobe • Prefers growth in highly oxygenated tissues (e.g. upper lobes of lung) • Slow growth- grown on Lowenstein Jensen medium-Rough, Tough and Buff colonies • Growth seen after 3-6 weeks of incubation • Facultative intracellular pathogen • Survival inside of macrophages • Able to establish life-long infection Z.N stain of sputum showing inflammatory exudate with acid fast bacilli Auramine Rhodamine stain of sputum showing fluorescent apple green, acid fast bacilli

11. M. tuberculosis – Virulence Factors • Cell wall components- very complex cell wall • Sulfolipids • Inhibition of phagosome-lysosome fusion and intracellular growth • Cord factor (trehalosedimycolate) • Inhibits leukocyte migration • Disrupts mitochondrial respiration and oxidative phosphorylation • Serpentine cord colonies • Tuberculin proteinsand mycolic acid • Delayed hypersensitivity and cell-mediated immunity  granulomas and caseation • No toxins – damage due to host immune response

12. PATHOGENESIS Primary tuberculosis is the response to the initial infection in a previously un-sensitized individual SOURCE: For pulmonary TB: Open (active) case of TB Latent Tuberculosis Seen as an intermediate and quiescent stage SOURCE: For bovine TB: Ingestion of contaminated milk (unpasteurized) Secondary TB/ Reactivation tuberculosis is the response to reinfection or reactivation of dormant lesion in a previously sensitized individual

13. Events in Primary Tuberculosis: 0-3 weeks Tubercle bacilli deposited in the alveoli (middle and lower lobes) MTB phagocytosed by non activated alveolar macrophages Intracellular existence and free multiplication in the cytoplasm of macrophages MTB-laden macrophages transported through lymphatics to the hilar lymph nodes and then to the bloodstream Dissemination of MTB to tissues like the liver, spleen, kidneys, bone, brain and apices of lungs GHONS FOCUS GHON COMPLEX

14. Events in Primary Tuberculosis: >3 weeks Macrophages release cytokines attracting T cells and TH1 response IFN-gamma activates macrophages to destroy MTB MTB proteins also trigger Delayed Type Hypersensitivity (DTH) and subsequent damage Granuloma composed of lymphocytes, macrophages, epitheloid cells and fibroblasts formed Caseous necrosis due to DTH Primary lesions heal by fibrosis with development of immunity Possible events

15. Predisposing factors: Immunosuppression precipitated by Alcoholism Diabetes HIV infection Old age Malnutrition Pregnancy Events in Reactivation Tuberculosis Reactivation Tuberculosis: Destructive cavities in the apices of lungs that may communicate with the wall of a bronchus. Other Organs: Kidneys, bones, meninges and brain

16. Disease Course Depends on Outcome of Battle between M. tuberculosis and Cellular Immune Defenses Latent (dormant) TB No disease; not infectious. Skin test (+); X-ray (+/-); Sputum (-) Primary TB In most cases the host prevails granulomas and foci fibrose, scar and calcify (Ghon complex) the infection remains clinically silent. 90% 10% 10% Progressive primary (active) TB Local disease or lesion break down spread of infection via lymph and blood to distant tissues Miliary TB. Infectious. Skin test (+); X-ray (+); Sputum (+) Secondary (reactivation) TB Impairment in immune status free organisms; possible dissemination. Infectious. Skin test (+); X-ray (+); Sputum (+)

17. Progression of TB

18. Granuloma formation (Tubercles) • Consists of epitheloid cells, sensitized T lymphocytes, multinucleated giant cells. • Central caseation necrosis due to DTH response • Healing by fibrosis Miliary mottling of organs showing multiple tubercles in Lung and Liver

19. Radiology and Pathology of TB

20. TB Radiology • Primary pattern • Unilateral consolidation • Middle/lower lobes, predilection for right lung • Segmental, lobar, multifocal • Unilateral lymphadenopathy, typically in children • Right hilar and paratracheal • Ipsilateral to lung consolidation • Pleural effusion • Unilateral, ipsilateral to pulmonary disease • Usually self-limited, resolves in several weeks • Atelectasis & hyperinflation in children • Progressive primary pattern • Cavitary consolidation • Bronchogenic dissemination (acinar nodules) • Post-primary pattern • Upper lobe apical/posterior segments and lower lobe superior segments, multiple segments involved • Poorly defined airspace disease • Heterogeneous consolidation ± cavitation • Pleural effusion: small, loculated, ± calcification

21. Active TB initial exam

22. PRIMARY TB: GHON COMPLEX SUBPLEURAL GRANULOMA GRANULOMA IN A HILAR LYMPH NODE GHON COMPLEX: THE PRIMARY FOCUS + THE HILAR LYMPH NODE DRAINING THE INFECTED AREA OF THE LUNG + THE LYMPHATIC CHANNEL IN BETWEEN. MOST PATIENTS WITH PRIMARY TUBERCULOSIS ARE ASYMPTOMATIC AND THE GRANULOMAS RESOLVE.

23. Active TB 2 years later MULTIPLE LESIONS AND CAVITATION

24. Active TB with a cavitary lesion

25. Active TB

26. Post-primary (reactivation) TB CAVITARY TUBERCULOSIS. There are large cavities in both apices (white arrows) and airspace disease at the left base (yellow arrow) on the chest radiograph. Coronal CT shows the thin-walled upper lobe cavities without air-fluid levels (blue arrows) and consolidation at the left base (green arrow). Nodular densities are scattered throughout both lungs.

27. POST PRIMARY (REACTIVATION) TB MORE SEVERE DISEASE IN THE UPPER LOBE CAVITY LARGE NUMBERS OF CAVITARY LESIONS HIGHLY INFECTIOUS PATIENT

28. POST PRIMARY ACTIVE TB WITH FLORID CAVITATION MULTIPLE CAVITARY CASEATING GRANULOMAS NECROTIZING GRANULOMATOUS INFLAMMATION EPITHELOID CELLS LANGHANS CELL LYMPHOCYTES

29. MILIARY TUBERCULOSIS MYRIAD MILLET SEED SIZED CASEATING GRANULOMAS H&E ZIEHL-NIELSEN

30. Sputum negative healed TB FIBROSIS AND VOLUME LOSS CECT BRONCHIECTASIS

31. OLD CALCIFIED TUBERCULOMA THICK FIBROUS PLEURAL ADHESIONS DISTORTED FIBROTIC LUNG PARENCHYMA WITH IRREGULAR TRACTION EMPHYSEMA

32. Lab Diagnosis of Active Pulmonary Tuberculosis • Laboratory – sputum analysis • Stains (presumptive ID) • Ziehl-Neelson or Kinyoun acid fast stain • Auramine-rhodamine fluorescent stain • Culture (confirmatory ID) • Lowenstein-Jensen media • Incubate 3-6 weeks @ 37°C • Differentiate from other mycobacteria • Production of niacin • Heat sensitive catalase (negative at 68°C) • Antibiotic susceptibility • Nucleic acid amplification tests = rapid

33. Other tests • Quantiferon TB Gold test: For measurement of IFN-gamma • Other serological tests are not recommended • Molecular Techniques-PCR- for rapid diagnosis • Gene Amplification techniques • Line Immunoassays for detection of Mtb DNA/ drug resistance

34. Tuberculin Skin Test (TST) • How to read: • Measure induration (not erythema) at 48-72 hrs • Record millimeters • Positive test: • ≥ 5mm for immunosuppressed including HIV, recent contacts • ≥ 10mm for all others with TB risk

35. Live vaccine from attenuated strains of Mycobacterium bovis Currently used in over 100 countries Given to children to protect against disseminated TB (~80% effective) TST reactivity often affected byBCG Use IGRA BCG Vaccine

36. Multidrug-Resistant Tuberculosis • Noncompliance is major factor in development of resistance • Multidrug-resistant TB (MDR-TB) = strains of tuberculosis that are resistant to the two first-line TB drugs - isoniazid and rifampicin • Extensive Drug Resistant TB (XDR-TB ) = MDR-TB with resistant to second-line medications: fluoroquinolones and at least one of three injectable drugs (i.e., amikacin, kanamycin, or capreomycin). Reference: WHO Global TB Report

37. Mycobacteria Other Than Tuberculosis MOTTS or atypical mycobacteria Usually acquired from environment Low level of pathogenicity • M. avium Complex (MAC) • M. avium and M. intracellulare • Transmission via inhalation or ingestion • Cause tuberculosis-like disease in immunocompromised • Opportunistic infection • Disseminated disease in AIDS patients • M. kansasii • TB-like disease • M. bovis • Causes tuberculosis in cattle but can infect humans • Transmission via infected milk or aerosol droplets • M. scrofulaceum • Causes lymphadenitis • Contaminated water • M. marinum • Causes soft tissue infection • “Fish tank granuloma” • Transmission thru abrasion

38. Other Acid Fast Organisms

39. Nocardiosis Nocardia asteroides

40. Nocardia asteroides • Microscopic • Branching GPR with “beaded” appearance • Filamentous • Weakly acid-fast • Transmission – airborne from soil • Cavitary bronchopulmonary nocardiosis • May disseminate to brain • Primary in immunocompromised • Treatment = sulfonamides or TMS

41. Questions?

42. References • www.cdc.gov/tb.html • www.who.int/tb/publications/global_report/gtbr14 • Pozniak A. Clinical manifestations and evaluation of pulmonary tuberculosis.UpToDate online. • Sterling T. Treatment of pulmonary tuberculosis in HIV-negative patients. UpToDate online. • Murray’s Medical Microbiology 8th edition • Ch.24 – Nocardiaasteroides • Ch.25 - Mycobacterium tuberculosis and MOTTS • Other References • UpToDate: https://www.uptodate.com • WHO: http://www.who.int/tb/

43. Antimycobacterial Drugs CDC-TB Infograph

44. Agents Used in the Treatment of Tuberculosis 1st -line agents 2nd -line agents Isoniazid Amikacin Ethionamide Cycloserine Ciprofloxacin Rifampin Capreomycin Levofloxacin Pyrazinamide Aminosalicylic acid Rifabutin Ethambutol Rifapentine Streptomycin Agents Used in the Treatment of Leprosy Rifampin Clofazimine Dapsone

46. Antimycobacterial Agents Mechanism of Action Drugs Isoniazid Inhibits mycolic acid synthesis Rifampin Inhibits bacterial RNA polymerase Ethambutol Inhibits arabinoglycan synthesis Pyrazinamide Inhibits fatty acid synthesis? Streptomycin Inhibits bacterial protein synthesis Dapsone Inhibits bacterial folate synthesis Clofazamine Inhibits bacterial DNA synthesis

47. Alternative 2nd-line Drugs for TB Protein synthesis inhibitor Amikacin Rifabutin RNA polymerase inhibitor Rifapentine Ciprofloxacin DNA synthesis inhibitor Levofloxacin Mycolic acid syn. inhibitor Ethionamide P- Aminosalicylic acid Folate synthesis inhibitor Protein synthesis inhibitor Capreomycin Cell wall synthesis inhibitor Cycloserine

48. Study Aid • Upon completion of this lecture, medical students should be able to • Summarize the unique structure of mycobacteria for therapeutic intervention • Summarize the standard treatment regimen for infections caused by mycobacteria • Comprehend the MOA of drugs used for infections caused by mycobacteria and mechanisms of drug resistance • List the major side effects/toxicities of drugs used for infections caused by mycobacteria • Evaluate the potential drug interactions with isoniazid and rifampin • Understand the unique use of rifabutine (but not refapentine) in HIV/TB p’ts • Comprehend the MOA of drugs used as alternative TB drugs • Know the use of clarithromycin or azithromycin for infection caused by mycobacterium-avium complex