TUBERCULOSIS...

1. TUBERCULOSIS... the disease in children and implications for the care of today’s child... from a clinician’s view. H. S. Patterson, M. D.

2. TB IN CHILDREN OBJECTIVES • Understand, in simple terms, the patho-physiology and clinical course of TB in children. • Understand the difference between TB infection and TB disease. • Understand how to make the diagnosis of TB in a child.

3. TB IN CHILDRENOUTLINE • historical and epidemiologic perspectives • diagnostic considerations • natural course • mortality/complications • why prophylaxis? • look alike

4. TUBERCULOSIS... The greatest killer of all time... The captain of all these men of death... ...during this century and the last, one billion people have died from tuberculosis

5. TUBERCULOSIS... “The White Plague” Oliver Wendell Holmes Sr, 1861

6. WHO is this famous Georgian who died of TB and how old was he when he died?

8. Leading causes of death in U.S. 1900 CAUSE DEATH RATE Flu & Pneumonia202/100,000 Tuberculosis 194/100,000 Diarrhea/Enteritis140/100,000

10. TB epidemiology in perspective • approximately 1/3 of the world’s population is infected with m. tuberculosis • there are approximately 8 million new cases of (active)TB per year, world wide • 2.9 million deaths occur annually from TB • 1987-1991, in US, number of cases of active TB in children less than 5 years of age, increased 49%

11. 2000 1500 1000 500 0 1985 1986 1987 1988 1989 1990 1991 Annual number of cases of tuberculosis in children less than 15 years of age in the United States

12. 2000 1900 1800 1700 1600 1981 1983 1985 1987 1989 Tuberculosis deaths by year, United States, 1980-1989 (National Health Statistics)

13. TB RISK FACTORS • crowding • decreased access to health care • lower socio-economic status • HIV • ? race

14. Historical TB

15. 1000 100 50 MORTALITY rate per 100,000 10 Tb evidenced in 4,000 BC 5 1 0.5 1700 1900 1750 1800 1850 1950 2000 YEAR Mortality from tuberculosis in developed countries

16. 1000 100 1804 Laennec associates lesions, describes “phthsis” 50 MORTALITY rate per 100,000 10 Tb evidenced in 4,000 BC 5 1 0.5 1700 1900 1750 1800 1850 1950 2000 YEAR Mortality from tuberculosis in developed countries

17. 1804 Laennec associates lesions, describes “phthsis” 1839, Shoenlein recognized “tubercle” as fundamental lesion, ergo “tuberculosis”. 1000 100 50 MORTALITY rate per 100,000 10 Tb evidenced in 4,000 BC 5 1 0.5 1700 1900 1750 1800 1850 1950 2000 YEAR Mortality from tuberculosis in developed countries

18. 1804 Laennec associates lesions, describes “phthsis” 1839, Shoenlein recognized “tubercle” as fundamental lesion, ergo “tuberculosis”. 1000 1882, Koch discovers mycobacterium tuberculosis 100 50 MORTALITY rate per 100,000 10 Tb evidenced in 4,000 BC 5 1 0.5 1700 1900 1750 1800 1850 1950 2000 YEAR Mortality from tuberculosis in developed countries

19. 1839, Shoenlein recognized “tubercle” as fundamental lesion, ergo “tuberculosis”. 1804 Laennec associates lesions, describes “phthsis” 1000 1882, Koch discovers mycobacterium tuberculosis 100 1917 Flu pandemic 50 MORTALITY rate per 100,000 10 Tb evidenced in 4,000 BC 5 1 0.5 1700 1900 1750 1800 1850 1950 2000 YEAR Mortality from tuberculosis in developed countries

20. 1839, Shoenlein recognized “tubercle” as fundamental lesion, ergo “tuberculosis”. 1804 Laennec associates lesions, describes “phthsis” 1000 1882, Koch discovers mycobacterium tuberculosis 100 1917 Flu pandemic 50 MORTALITY rate per 100,000 10 Tb evidenced in 4,000 BC 5 1946, Streptomycin used as antibiotic 1 0.5 1700 1900 1750 1800 1850 1950 2000 YEAR Mortality from tuberculosis in developed countries

21. Upstate New York

22. 30000 26000 REPORTED TB CASES US actual 22000 18000 expected 1981 1983 1985 1987 YEAR

23. 30000 26000 REPORTED TB CASES US actual 22000 HIV related 18000 expected 1981 1983 1985 1987 YEAR

24. Natural history of tuberculosis in a newly infected (adult) contact (infection is not necessarily disease) NO INFECTION CONTACT (90%) NO DISEASE Defenses INFECTION (5%) Cell-mediated immunity EARLY DISEASE DISEASE (5%) LATE DISEASE

25. DIAGNOSIS: CMI NO INFECTION CONTACT (90%) NO DISEASE Defenses INFECTION cell-mediated immunity (5%) EARLY DISEASE DISEASE (5%) LATE DISEASE

26. DIAGNOSIS: CMI NO INFECTION CONTACT (90%) NO DISEASE Defenses INFECTION cell-mediated immunity (5%) EARLY DISEASE DISEASE (5%) LATE DISEASE PPD positive

27. The TB Skin Test: MATERIALS • OLD TUBERCULIN • culture of TB bacillus in glycol peptone broth • TB “tine” test • PURIFIED PROTEIN DERIVATIVE (PPD) • TB bacillus grown in Long’s media, filtered after heating • adopted by WHO as standard in 1950 • PPD-S 1952 • dose = 5 IU

28. The TB (Mantoux) Skin Test • Intra-dermal • quality control important • trained practioner necessary • Delayed hypersensitivity • cell mediated • 48-72 hours • False negative • immuno-compromized conditions • measles/measles immunizations • Nonspecific reactions • increase >10 IU • cross reactions, atypical MB

29. Factors causing decreased ability to respond to tuberculin • Factors related to the person being tested • Infections • Viral (measles, mumps, chickenpox) • Bacterial (typhoid fever, brucelosis, typhus, pertussis, overwhelming TB, • Fungal (South American blastomycosis) • Live virus vaccinations (MMR) • Metabolic derangements (chronic renal failure) • Nutritional factors (severe protein depletion) • Diseases affecting lymphid organs (Hodgkin’s lymphoma, chronic lymphocytic leukemia, sarcoidosis) • Drugs (corticosteroids, other immunosuppressive agents) • Age (newborn, elderly) • Recent overwhelming infection with M. tuberculosis • Stress (surgery, burns, mental illness, graft versus host reactions) • Factors related to the tuberculin used • Factors related to the method of administration • Factors related to reading the test and recording results

30. Indications for skin test screening • Persons with signs and/or symptoms suggestive of tuberculosis disease • Recent contacts of persons known or suspected to have tuberculosis • Persons with undiagnosed upper lobe fibrotic lesions • Persons infected with HIV • Alcoholics and intravenous drug abusers • Persons with medical conditions known to increase the risk of disesase if infection has occurred: • silicosis, gastrectomy, jejunoileal bypasss, significant weight loss below IBW, chronic renal failure, diabetes mellitus, high dose corticosteroid treatment or other immunosuppressive therapy, leukemia, lymphoma, malignancy • Groups at high risk of infection: • Latin America, Oceana, medically underserved populations, residents of long term care facilities • Groups that would pose a significant risk to others if diseased: employees of health care facilities, schools, child care facilities ATS/CDC

31. TB PATHOPHYSIOLOGY • systemic infection • primary infection/disease • progressive primary disease • miliary disease • meningitis • chronic TB (re-activation)

32. Inhalation of Infected Droplet Nuclei 1) skin test sensitization non-specific bronchopneumonia 2) resistance to exogenous reinfection 3) lympho-hematogenous spread complete resolution (rare) progression healing with granuloma formation massive necrosis (rare) stable breakdown with development of (re-activation)TB DISEASE

33. TB: PRIMARY Infection • 95% of cases begin with pulmonary focus • usually a SINGLE focus • hypersensitivity develops 2 to 6 weeks • until then, focus may grow larger • hypersensitivity brings caseation

34. Tissue Specimens Obtained at Autopsy from the Patient Jha, A. K. et al. N Engl J Med 2004;350:2399-2404

35. PRIMARY Infection: Lympho-hematogenous spread • 8-14 weeks after onset of TB • usually occult • Mantoux positive during this phase • body wide seeding occurs during this phase • bone, kidney, meninges etc. • 3% of children with nl CXR’s develop calcifications in lung apices (SIMON FOCI)

36. Jha, A. K. et al. N Engl J Med 2004;350:2399-2404

38. PRIMARY TB:endo-bronchial consequences • lymph nodes draining primary infection site become involved • lymph node capsule becomes adherent to bronchial wall • infection can progress to ulceration into the bronchial wall • bronchial compression occurs with more than one node at same level • with healing, bronchial constriction/stenosis can occur

39. INFECTION TO ENDO-BRONCHIAL DISEASE TOSTENOSIS

40. HEALED PRIMARY INFECTION SIMON FOCI CALCIFIED nodes and peripheral lesion (Ghon complex) other VISCERAL sites

41. infection lympho-hematogenous spread healed PRIMARY infection USUAL PROGRESSION OF PRIMARY INFECTION

42. PROGRESSIVE PRIMARY TB(DISEASE) • occasional (3.7%) local progression, despite hypersensitivity (more common in younger pt) • can be cavitary • can have endo-bronchial spread • similar in appearance to adult type, “reactivation” disease • 2/3 of cases progress to death in the untreated

43. PROGRESSIVE PRIMARY DISEASE lymph node involvement cavitation pleural effusion

44. Progressive Primary Disease

45. ENDOBRONCHIAL SPREAD WITH SUBSEQUENT BRONCHOPNEUMONIA

46. Disseminated TB pneumonia

47. MILIARYDiseaseGeneralized Hematogenous Tuberculosis • generalized dissemination through bloodstream • caseous focus ruptures into blood vessel • growth of tubercle within the blood vessel • may be acute, occult or chronic • uniformly fatal if not treated • rare • usually occurs in the first 4 months after primary infection

48. MILIARYDisease • millet seed appearance on X-ray • Mantoux positive? • Most children still have active primary complex when miliary disease strikes • most develop meningitis

49. Major sites of extra-pulmonary tuberculosis among children in the United States SITES % Avg. Age lymphatics 67 5y meninges 13 3y pleura 6 16y miliary 5 1y skeletal 4 5y other 5 Clin Chest Med 1989, Am. Rev. Resp. Dis, 1990

50. TB MENINGITIS • primary seeding • caseous lesion adjacent meninges • growth/discharge • usually insidious • prophylaxis is preventive