Tuberculosis

1. Tuberculosis January 28th, 2008 Jasemine Yang and Tamara Bodnar M. tuberculosis

2. A Brief History of Tuberculosis (TB) • Tuberculosis (phthisis) described since the time of Hippocrates (460 BC - 370 BC) • 1689: Doctor Richard Morton used the term “consumption” to denote TB. • Second half of the 17th century: high death rates from TB in Europe. • 1722: Doctor Benjamin Marten proposed that TB could be transmitted in the air and described TB as being caused by “wonderfully minute living creatures” • End of 19th century to the start of 20th century: Principal cause of death in Europe was TB. • The romantic Era of TB “Queen Guinevere” painted by William Morris

3. A Brief History of Tuberculosis (TB) • 1865 Jean-Antoine Villemin: confirmed that • TB is contagious. • Robert Koch: • 1882: Isolated and cultured M. tuberculosis. • 1890: Announced the discovery of tuberculin. • Developed staining methods used to identify the bacteria. • 1905: Received the Nobel Prize • Bacteriologist Paul Ehrlich developed Ziehl- • Neelsen staining. • Late 1800’s: Edward Livingston Trudeau • established “Adirondack Cottage • Sanatorium”, first TB sanatorium in the US. Visualization of M. tuberculosis using the Ziehl-Neelsen stain

4. A Brief History of Tuberculosis (TB) • 1896 Theobald Smith demonstrated that bovine TB is caused by M. bovis. • 1908 Albert Calmette and Camille Guérin isolated M. bovis and grew it in ox bile. • Identified a morphological variant of M. bovis found to be avirulent, conferred immunity against M. tuberculosis. • Lead to the BCG vaccine (bacilli Calmette-Guérin). • Development of antibiotics to combat infection: • 1947: streptomycin, 1952: isoniazid • The majority of drugs used to combat infection were identified between 1945 and 1967. • No new drugs developed since the 1980’s • Reoccurrence of TB for two main reasons: 1)HIV/AIDS pandemic 2)Development of drug resistance M. bovis

5. Tuberculosis in Humans • Reservoir: Humans • Transmission: Airborne disease (aerosol transmission) • Symptoms: Latent TB infection:Active TB infection: No symptoms Bad cough *Cannot spread TB Coughing up blood/sputum Chest pain Loss of appetite Weight loss Fever Chills Night sweats Swollen glands *Contagious • Extra-pulmonary TB: Symptoms depend on location of infection • General symptoms: fatigue, fever, loss of appetite, weight loss. • TB of lymph nodes: swelling of lymph nodes • TB meningitis: neurological symptoms including headache • Spinal TB: Mobility impairments, pain

6. Mycobacterium Tuberculosis • General Characteristics • Family – Myobacteria • Gram-positive aerobic rod-shaped bacilli • “Acid fast” bacteria • Lack of spore formation and toxin production • No capsule, flagellum (non-motile) • Generation time of 18- 24 hours but requires 3-4 weeks for visual colonies SEM of M. tuberculosis • Pathological Features • Principle cause of Human Tuberculosis • Intracellular pathogen (alveolar macrophages) • Waxy, thick, complex cellular envelope • Cell envelope components ex) sulfolipids • Produces tubercles, localized lesions of M. tuberculosis M. Tuberculosis (stained in purple)

7. Mycobacterial Cellular Envelope • General Features • Thick, waxy and complex • Higher fluidity in more external regions than internal regions • Relatively impermeable to hydrophilic solutes • Contain porins (selective cationic channels) • Main Components • Peptidoglycan •  contains N-glycolylmuramic acid instead of N-acetylmuramic acid • Arabinogalactan • Mycolic Acids (60% of cellular envelope) • Lipoarabinomannan (LAM)

8. Mycobacterial Cellular Envelope

9. Contribution of Mycobacterial Cellular Envelope to Pathogenesis • Resistance to Drying and Other Environmental Factors • Thick, waxy nature of cellular envelope protects M. tuberculosis from drying, alkali conditions, and chemical disinfectants • Hinders entrance of antimicrobial agents • Entry into Host Cells • Lipoarabinomannan (LAM) binds to mannose receptors on alveolar macropages leading to entry into the cell • Interference of Host Immune Response • - Glycolipids and sulfolipids decrease the effects of oxidative cytotoxic mechanism • Inhibition of phagosome and lysosome fusion inside macrophage • Waxy cellular envelope prevents acidification of the bacteria inside the phagosome

10. Factors Affecting Pathogenicity • Active Infection • Only individuals with an active infection can transmit the disease • Transmission • Aerosolized droplets need to be <10μm in order to evade the ciliated epithelium of the lung to establish infection in the terminal alveoli • Growth & Structure • Only require a very few number of bacteria to establish an infection (1-10 bacteria) • Slow generation time M. Tuberculosis in sputum(stained in red)

11. Variability of Infection Rates • Exposure Time • Most infected individuals expel relatively few bacilli, transmission of TB usually occurs only after prolonged exposure to someone with active TB. • On average, 50% of people are likely to become infected with TB if they spend 8hrs/day for six months or 24hrs/day for two months working or living with someone with active TB. • Health of Individuals • Active TB typically occur in individuals whose immune systems have been weakened by age, disease, improper nutrition or use of immunosuppresive drugs.

12. Tuberculosis – Disease Progression • Primary Infection • In healthy individuals… • M. tuberculosis phagocytosed by alveolar macrophages leading to intracellular proliferation and tubercle formation • Cell-mediated response develops and eliminates most of the bacilli in 2-6 weeks • Commonly asymptomatic • OR • M. tuberculosis can remain dormant intracellularly

13. Tuberculosis – Disease Progression • Primary Infection • Immunocomprimised Individuals… • Infection leads usually leads to progressive primary tuberculosis, where the pathogen breaks out of the tubercles in the alveoli and cause active disease • Active disease leads to chronic inflammation • Death of pathogen and pulmonary cells can lead to Gohn complex and granuloma formation • May lead to extrapulmonary tuberculosis (TB infection outside the lung in the CNS and lymph nodes)

14. Latent Tuberculosis Infections • Following exposure to TB: Inhaled bacilli usually destroyed by host’s immune system (90-95% of the time). • Healthy person: Recruitment of T-cells and macrophages which results in controlling the infection. • Some bacilli can establish infection in macrophages (phagosomes) leading to host immune response • Bacilli forced into an inactive (latent), non-replicating state. • Survive intracellularly: prevent phagosome-lysosome fusion. • Infection contained but not eradicated. • The dormant bacteria are still viable, can be re-activated: Approximately 10% of latent infections will develop into active TB if left untreated. • Factors that lead to re-activation of the bacteria: HIV co-infection, aging, cancer, diabetes etc M. Tuberculosis colonies

15. Tuberculosis – Disease Progression • Note… • Infection does not mean disease! • Infection can lead to active disease or dormant state of pathogen • Active disease develops differently (Healthy individuals VS. Immunocomprimised individuals) • Summary of TB Infection in Alverolar Macrophages • http://www.nature.com/nrmicro/animation/imp_animation/index.html

16. Treatment Antibacterial chemotherapy: • Combination of first and second line drugs for the first 2 months which could include: • Isoniazid • Rifampicin • Pyrazinamide • Streptomycin or Ethambutol • Next 4 months, combination of: • Isoniazid • Rifampicin • Early resistance to isoniazid: other first-line drugs such as ethambutol, streptomycin, pyrazinamide and fluoroquinolones can be added to drug arsenal (treatment period also extended). • These drugs are relatively effective in killing the bacteria, however, they also produce a wide variety of side effects.

17. Treatment First line drugs: - Bactericidal agents: kill active bacteria, important in the early stages of infection. Second line drugs: - Bacteriostatic: hinder bacterial growth. - Strengthen treatment in the case of resistant bacteria. - Less efficient and generally more toxic than first line drugs. Inappropriate chemotherapy: • Monotherapy (single drug treatment) • Decreased treatment period • Low absorption of drugs

18. Treatment

19. Drug Resistance and Tuberculosis • M. tuberculosis: naturally resistant to certain antibiotics due to presence of: • Drug-modifying enzymes • Drug-efflux systems • Hydrophobic cell wall • Mycobacteria undergo natural mutations which can lead to development of drug resistance. • TB is treated by administration of combination chemotherapy: decreases probability of development of drug resistance. • Development of increasingly resistant strains mainly due to: Patient non-compliance

20. MDR and XDR Tuberculosis MDR: Multidrug-resistant strains: • Strains of tuberculosis resistant at least to rifampicin and isoniazid. • Mortality rate: 40-60% • Estimated that 50 million people are infected with MDR-TB. • MDR-TB is approximately 125 times more expensive to treat than drug susceptible TB. • XDR: Extensively-drug resistant strains: • Strainsof tuberculosis resistant to rifampicin, • isoniazid and at least three of the following • classes of second-line drugs: aminoglycosides, • polypetides, fluoroquinolones, thioamides, • cycloserine and para-aminosalicylic acid.

21. MDR and XDR Tuberculosis • Emergence due to lack of patient compliance during TB treatment and inappropriate administration of TB drugs. • Results in more aggressive forms of TB. • Drug resistance does not increase infectiousness. • MDR and XDR-TB: uncommon in developing nations lacking TB drugs (high drug-susceptible TB rates) • MDR and XDR-TB rates are higher in developed nations with access to anti-TB drugs.

22. Tuberculosis and HIV/AIDS • HIV pandemic has reversed much of the progress made in the past few decades in combating TB. • People with latent TB have a 10-20% of developing active TB in their lifetime. People with HIV and latent TB are 100 times more likely to develop active TB. • HIV/AIDS leads to a compromised immune system: • HIV infects CD4+ T cells, macrophages, dendritic cells. • Result: decreased CD4+ T cells due to apoptosis of infected cells, CD8+T cell mediated killing of infected cells • The numbers of CD4+ T cells progressively decline (loss of cell-mediated immunity) and the body is much more susceptible to infection T cell

23. Tuberculosis and HIV/AIDS • A person with HIV/AIDS will have a harder time fighting off the M. tuberculosis infection due to a compromised immune system. • HIV infection can cause latentM. tuberculosis infection to become reactivated. • TB is the leading cause of death for people with HIV/AIDS: mean survival rate is 430 days. • MDR and XDR-TB and HIV/AIDS: • Additional symptoms: excessive weight loss, respiratory problems (including the formation of lesions in the lungs). • Mean survival rate: 45 days.

24. Discussion: The Challenges of TB Control • Expansion and enhancement: • Legistlation/planning/human resources/management/training • Drug Resistance Surveillance (DRS) • TB treatment and program management guidelines • An effective drug supply and management system • Global Drug Facility • Revised TB recording and reporting forms • Electronic recording and reporting systems • Global TB Control Report • TB epidemiology and surveillance online workshop • Contribute to health system strengthening • Engage all care providers • Empower people with TB • Community and patient involvement in TB care • Address TB/HIV, MDR/XDR-TB and other challenges: • TB challenges • MDR-TB • XDR-TB • TB/HIV • TB and air travel • TB and poverty • TB and gender • TB and prisons • Enable and promote research: • Drug research • Vaccine research • M. tuberculosis research • Development of new diagnostic tools for detecting latent, pulmonary and extra-pulmonary TB. The WHO has developed a “Stop TB Strategy” outlining some the issues that need to be addressed in order to stop the spread of disease:

25. Discussion: The Challenges of TB Control From this list… • What do you consider the top 5 most important issues? • Are there any you feel are unimportant or relatively unimportant? • Which do you feel would be the hardest to implement or attain?

26. Discussion: The Challenges of TB Control The WHO has multiple goals concerning the control of TB including: • “By 2005: detect at least 70% of new sputum smear-positive TB cases and cure at least 85% of these cases”. • “By 2015: reduce prevalence of and death due to TB by 50% relative to 1990”. • “By 2050: eliminate TB as a public health problem (<1 case per million population)”. • What key issues need to be resolved and what developments need to occur in order to reach these goals?  Start by examining the “Stop TB strategy” list.

27. Discussion: The Challenges of TB Control The WHO has multiple goals concerning the control of TB including: • “By 2005: detect at least 70% of new sputum smear-positive TB cases and cure at least 85% of these cases”. • “By 2015: reduce prevalence of and death due to TB by 50% relative to 1990”. • “By 2050: eliminate TB as a public health problem (<1 case per million population)”. • What key issues need to be resolved and what developments need to occur in order to reach these goals?  Start by examining the “Stop TB strategy” list.

28. Discussion: The Challenges of TB Control • Based on these graphs from the WHO, what do you think the correlation is between gender and rates of tuberculosis infection? • How should this be taken into consideration when planning programs against TB?

29. Discussion: The Challenges of TB Control • Why do you think there are more TB-dedicated facilities at the national or provincial level? • Do you think this may have an effect on the prevalence of tuberculosis in these high-burden countries?

30. Why Does TB Need Global Attention? • Deadliest infectious diseases affecting humans. • Approximately 1/3 of the world population is infected with M. tuberculosis. • 8-10 million new cases of TB per year. • Leading cause of death among people with HIV/AIDS. • Greatest infectious killer of women of child-bearing age. • Results in approximately 3 million deaths per year. • 26% of preventable deaths are due to TB. • 7% of all deaths are due to TB. • New anti-TB agents needed to combat TB due to high prevalence of drug-resistant strains. • In 1993 the WHO declared TB a “global public health emergency” (only disease thus far to be given this designation).