Tuberculosis & other mycobacterial infections II

1. Tuberculosis & other mycobacterial infections II Assoc Prof Meral Sönmezoğlu Division of Infectious Diseases Yeditepe University Hospital

4. Tuberculosis • Important new findings at the global level are: • The absolute number of TB cases has been fallingsince 2006 (rather than rising slowly as indicated in previous global reports); • TB incidence rates have been falling since 2002 (twoyears earlier than previously suggested); • Estimates of the number of deaths from TB each year have been revised downwards; • In 2009 there were almost 10 million children who wereorphans as a result of parental deaths caused by TB.

5. Tuberculosis • In 2010, there were 8.8 million (range, 8.5–9.2 million)incident cases of TB, • 1.1 million (range, 0.9–1.2 million)deaths from TB among HIV-negative people and • anadditional 0.35 million (range, 0.32–0.39 million) deaths from HIV-associated TB.

6. Tuberculosis: current problems • About 3.8 million cases per year; 90% (and 98% of the 3 million deaths) are in developing countries • Multidrug resistance (“MDR-TB”) • AIDS: atypical presentations and distribution • Nosocomial spread • Foreign-born

7. Millennium Development Goals set for 2015 Goal : Combat HIV/AIDS, malaria and other diseases Target: Halt and begin to reverse the incidence of malaria and other major diseases Indicator:Incidence, prevalence and death rates associated with TB Indicator: Proportion of TB cases detected and cured under DOTS Stop TB Partnership targets set for 2015 and 2050 By 2015: Reduce prevalence and death rates by 50%,compared with their levels in 1990 By 2050: Reduce the global incidence of active TB casesto <1 case per 1 million population per year

8. World TB Day World TB Day World TB Day 24th March 1882 when Dr Robert Koch astounded the scientific community by announcing that he had discovered the cause of tuberculosis, the TB bacillus • He was presented with the Nobel Prize in Physiology or Medicine in 1905 "for his investigations and discoveries in relation to tuberculosis." • Themes by • 2013: Stop TB in my lifetime Call for a world free of TB. • 2012: Stop TB in my lifetime Call for a world free of TB. • 2011: On the move against TB: Transforming the fight towards elimination • 2010: On the move against TB: Innovate towards action • 2009: I am stopping TB

13. Prevalence of MDR Tuberculosis among New Cases of Tuberculosis, 2007, and Countries with at Least One Reported Case of XDR Tuberculosis as of December 2008 Donald P and van Helden P. N Engl J Med 2009;360:2393-2395

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23. Extrapulmonary tuberculosis

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25. Mycobacterium tuberculosis • MTB is a bacterium belonging to the Mycobacterium genus • Its identification is based on the following characteristics:shape of the colonies, growth rate, and biochemical reactivity. • subdivided in two main groups based ontheir growth rates (fast vs. slow)

26. Mycobacterium tuberculosis • The rapidly growing Mycobacterium species (Mycobacterium abscessus, M. fortuitum, M. porcinum), whereas the majority are nonpathogenic • Majority of the slowly growing Mycobacteriumspecies are pathogenic for humans and/or animals (e.g., allthe species of the MTB complex [MTBC], M. leprae, M. ulcerans,M. avium), and only a few of them are nonpathogenic(e.g., M. terrae, M. gordonae). • MTB complex: MTB (Koch,1882), M. bovis (Karlsen and Lessel, 1970), M. africanum [25], M. microti (Reed, 1957),“M. canettii’

27. Mycobacterium tuberculosis • rod-shaped bacteria (0.2–0.6 m wide, 1–10 m long), nonmotile, nonencapsulated,Gram-positive, • aerobes (growing most successfully in tissues with ahigh oxygen content such as lungs), or facultative anaerobes. • They are facultative intracellular pathogens, usually infectingmononuclear phagocytes (e.g., macrophages).

28. Mycobacterium tuberculosis • An obligate aerobe: prefers P02 of 130 torr • Replicates every 20 hours • Natural resistance to one drug is one in every 105 to 107 cells • Natural resistance to two or more drugs is 1 in every 109 to 1012 cells

29. Tuberculosis: the basics • The Mycobacterium tuberculosis complex: M. tuberculosis, M. bovis, M. africanum • Transmitted primarily by airborne droplet nuclei • Persons with positive AFB sputum smears are especially effective transmitters • Between 5% and 15% of infected persons will develop active disease (involving any organ) within two years

30. Tuberculosis: the basics (2) • Populations at increased risk of infection: medically-underserved, low-income groups; immigrants; residents of long-term care or correctional facilities • Infected persons with increased risk of active disease: close contacts of cases; children < 5 years old; persons with chronic diseases (renal failure; silicosis; diabetes); immunosuppressed; HIV-positive persons

31. Immunology of tuberculosis • Tubercle bacillus + macrophages --> processed antigen • Antigen recognition by lymphocytes --> activated lymphocytes --> lymphokines • Lymphokines--> attraction, stimulation, and retention of macrophages at antigen site • Activated macrophages--> lytic enzymes with mycobactericidal but also tissue-necrosing capacity

32. Mycobacterium tuberculosis(MTB) enters the host within inhaled droplets.

33. Immunology of tuberculosis (2) • Interferon-gamma probably stimulates macrophages to produce interferon-alfa and 1,25-dihydroxyvitamin D, both of which are mycobacterial inhibitors • Cytokines secreted by alveolar macrophages: interleukin 1 (fever); interleukin 6 (hyperglobulinemia), and tumor necrosis factor alpha (killing of organisms, granuloma formation, fever and weight loss)

35. Primary tuberculous infection • Inhalation leads to infection at periphery of middle lung zone • Pneumonia 2 to 6 weeks after infection followed by lymphohematogenous dissemination • Cell-mediated immunity (manifested by positive PPD) usually contains the infection • Some organisms remain viable

36. Pathogenesis of tuberculosis

37. Reactivation of tuberculosis • Occurs most often in persons > 50 years of age; more common in men • Higher risk in elderly persons and in those with malnutrition, diabetes mellitus, post-gastrectomy, immunocompromise, alcoholism, HIV infection, or corticosteroid therapy

38. Residua of primary infection • Ghon complex (after Anton Ghon, German bacteriologist): calcified peripheral focus of tuberculous infection with calcified regional (hilar) lymph node (also called Ranke complex) • Simon focus (after Georg Simon, German pediatrician): focus at apex of lung, containing viable organisms and manifested on x-ray as “fibrous cap”

39. Axioms on Simon foci • “If humans did not have apices to their lungs, the tubercle bacillus would not have survived as a human pathogen.” • “Once a Simon focus has formed, one will eventually die of tuberculosis if something else doesn’t cause death first.”

40. Caseous necrosis of tuberculosis • This walled-off, friable, cheesy nodule in the subapical region (a Simon focus) develops from organisms spread hematogenously from the initial focus of infection in the lower half of the lung. Reactivation of this lesion would probably destroy the capsule, and the caseous material would be expectorated leaving a cavity.

41. Tuberculous pleuritis non-necrotizing granulomas the Langhans' giant cells, the epithelioid cells, and the lymphocytes.

42. Progression to active tuberculosis • One year after infection: approximately 5% • Thereafter: approximately 5% (lifetime) • It now seems that many people eventually outlive their tubercle bacilli and are consequently vulnerable to reinfection (Stead, studies in Arkansas, early 1980s) • Tuberculin-positive persons with HIV infection: risk is 7% to 10% per year

43. Insights from genotyping of M. tuberculosis isolates (N Engl J Med 2003; 349: 1149-1155) • Previously, it was thought that 90% of TB cases in industrialized nations resulted from reactivation of infection acquired in remote past. • It now seems that recent transmission causes 40% to 50% of TB cases in urban areas.

44. The cavity (1) • Formation of the cavity is the pivotal event in the evolution of pulmonary tuberculosis. • Mortality of cavitary pulmonary tuberculosis without treatment approaches 90%. • All therapies prior to 1948 were aimed at closing cavities.

48. The cavity (2) • Even healed, cavities are unstable. • The walls of cavities contain extensive sheets of bacilli (up to 1011 bacilli/gram). • The cavity is thinnest at the point of penetration of bronchi. • Open cavities may persist for years, constantly draining bacilli into the rest of the bronchial tree.

49. Complications of pulmonary tuberculosis • Cough, fever, night sweats, weight loss, anemia • Massive hemoptysis (erosion of a vessel in the wall of a cavity; a dilated vessel in a cavity (Rasmussen’s aneurysm; or an aspergilloma) • Progressive pulmonary disease, rarely ARDS • Hyponatremia due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

50. Major syndromes of extrapulmonary tuberculosis • Disseminated (miliary) tuberculosis • “Serosal” tuberculosis (anatomic spaces or cavities): pleurisy, pericarditis, meningitis, peritonitis, arthritis • Tuberculosis of solid organs: renal (genitourinary), osteomyelitis, adrenal glands (Addison’s disease), lymph nodes