Tuberculosis and other Mycobacterial Infections

1. Tuberculosis and other Mycobacterial Infections Charles S. Bryan, M.D. November 27, 2007

5. 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. Number of reported cases of TB by year of diagnosis, USA, 1982-2003

8. Number and percentage of cases of TB among foreign-born persons, by year of diagnosis, USA, 1986-2003

9. TB incidence among five racial/ethnic populations, USA, 2003

10. 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

11. 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

12. 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

13. 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

14. 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)

16. Pathogenesis of tuberculosis

17. 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

18. 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

19. 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”

20. 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.”

21. 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

22. 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.

23. 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.

27. 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.

29. 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)

30. 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

33. Miliary tuberculosis: diagnostic aids • Repeat physical examination: choroidal tubercles, palpable lymph nodes • Repeat CXR and tuberculin test • Cultures: sputum (up to 63% positive), urine, bone marrow, CSF, gastric aspirate, pleural fluid • Biopsy: palpable nodes, marrow, liver • Therapeutic trial

34. “Cryptic miliary tuberculosis” • An occult illness with gradual decline in general health • Often no significant fever • Non-reactive tuberculin skin test • Normal chest x-ray

38. Frequency order of extrapulmonary sites 1. Lymph node 2. Pleura 3. Genitourinary tract 4. Bone and joints 5. Meninges 6. Peritoneum

39. Tuberculous pleurisy • Subpleural focus ruptures into the pleural space • Usually younger adults, 3 to 7 months after primary tuberculous infection • Abrupt or insidious onset. DDx: pneumonia, pulmonary infarct, tumor, others • Natural history untreated: 65% of 141 patients developed active tbc (Roper & Waring)

40. Tuberculous meningitis • Rupture of subependymal tubercle into subarachnoid space (“Rich focus”; Rich and McCormack, 1933) • The intrathecal tuberculin reaction (instillation of PPD material into CSF of PPD-positive volunteers) • Usually occurs within first 6 months of infection; now seen in older adults

41. Tuberculous pericarditis • Rupture of a tuberculous mediastinal lymph node into the pericardial sac • Mortality 80% to 90% without treatment. Major problems even with appropriate Rx • Diagnosis is difficult to make short of total pericardiectomy • Constrictive pericarditis • Can extend into myocardium --> fiber atrophy

42. Tuberculous peritonitis • Onset is usually insidious. Mortality 45% to 55% untreated but as low as 0% to 4% with treatment • Polar types: plastic or adhesive type (“doughy abdomen”) and exudative or serous peritonitis with ascites • Presentations: debilitating FUO; chronic abdominal pain; ascites of unknown origin

43. Tuberculous arthritis • Tuberculous focus in bone ruptures into joint space; trauma predisposes • Adults: spine 50%, hips 15% • Children: Knees 15% • Insidious joint pain and swelling, most often involving large weight-bearing joints • Absence of proteolytic enzymes explains preservation of joint space

44. Genitourinary tuberculosis • Tubercle of the glomerulus ruptures into the calyceal system • May progress to involve the entire kidney (“autonephrectomy”) and/or may spread throughout the GU tract (prostatitis, epididymitis, salpingitis) • Insidious onset

45. Tuberculous osteomyelitis • Subchondral osteoporosis with surrounding ring of sclerosis • Spine: anterior involvement of vertebral bodies with disk collapse (Pott’s disease) • Suspect: Monoarticular arthritis of insidious onset; paraspinous mass; back pain

46. Tuberculosis of the adrenal glands (Addison’s disease) • Tuberculosis formerly the major cause of the disease as described by Thomas Addison (now rare; most common cause is idiopathic [autoimmune]) • Wasting, hyperpigmentation, low blood pressure, hyponatremia, hyperkalemia

47. Tuberculosis in HIV-positive patients • Present in 5% to 35% of patients diagnosed with AIDS • Precedes diagnosis of AIDS in 67% of patients • Although most of these cases result from reactivation, CXR often resembles progressive primary tuberculosis • Multiple drug resistance a major problem

49. AFB smears • Three morning specimens • Fluorescent methods are more sensitive than traditional Kinyoun or Ziehl-Neelsen method • Predictive value of a positive test decreases strikingly as prevalence of the disease decreases (Bayes’ s theorem)