Tuberculosis

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Tuberculosis

  1. 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. 2. TB IN CHILDREN OBJECTIVES <ul><li>Understand, in simple terms, the patho-physiology and clinical course of TB in children. </li></ul><ul><li>Understand the difference between TB infection and TB disease . </li></ul><ul><li>Understand how to make the diagnosis of TB in a child. </li></ul>
  3. 3. TB IN CHILDREN OUTLINE <ul><li>historical and epidemiologic perspectives </li></ul><ul><li>diagnostic considerations </li></ul><ul><li>natural course </li></ul><ul><li>mortality/complications </li></ul><ul><li>why prophylaxis? </li></ul><ul><li>look alike </li></ul>
  4. 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. 5. TUBERCULOSIS... <ul><li>“ The White Plague” </li></ul><ul><ul><ul><li>Oliver Wendell Holmes Sr, 1861 </li></ul></ul></ul>
  6. 6. WHO is this famous Georgian who died of TB and how old was he when he died?
  7. 8. Leading causes of death in U.S. 1900 <ul><li>CAUSE DEATH RATE </li></ul><ul><li>Flu & Pneumonia 202/100,000 </li></ul><ul><li>Tuberculosis 194/100,000 </li></ul><ul><li>Diarrhea/Enteritis 140/100,000 </li></ul>
  8. 10. TB epidemiology in perspective <ul><li>approximately 1/3 of the world’s population is infected with m. tuberculosis </li></ul><ul><li>there are approximately 8 million new cases of (active) TB per year, world wide </li></ul><ul><li>2.9 million deaths occur annually from TB </li></ul><ul><li>1987-1991, in US, number of cases of active TB in children less than 5 years of age, increased 49% </li></ul>
  9. 11. 0 500 1000 1500 2000 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
  10. 12. 1600 1700 1800 1900 2000 1981 1983 1985 1987 1989 Tuberculosis deaths by year, United States, 1980-1989 (National Health Statistics)
  11. 13. TB RISK FACTORS <ul><li>crowding </li></ul><ul><li>decreased access to health care </li></ul><ul><li>lower socio-economic status </li></ul><ul><li>HIV </li></ul><ul><li>? race </li></ul>
  12. 14. Historical TB
  13. 15. 0.5 100 1000 1700 1750 1800 1850 1900 1950 2000 1 5 10 50 YEAR MORTALITY rate per 100,000 Mortality from tuberculosis in developed countries Tb evidenced in 4,000 BC
  14. 16. 0.5 100 1000 1700 1750 1800 1850 1900 1950 2000 1 5 10 50 YEAR MORTALITY rate per 100,000 Mortality from tuberculosis in developed countries Tb evidenced in 4,000 BC 1804 Laennec associates lesions, describes “phthsis”
  15. 17. 0.5 100 1000 1700 1750 1800 1850 1900 1950 2000 1 5 10 50 YEAR MORTALITY rate per 100,000 Mortality from tuberculosis in developed countries Tb evidenced in 4,000 BC 1839, Shoenlein recognized “tubercle” as fundamental lesion, ergo “tuberculosis” . 1804 Laennec associates lesions, describes “phthsis”
  16. 18. 0.5 100 1000 1700 1750 1800 1850 1900 1950 2000 1 5 10 50 YEAR MORTALITY rate per 100,000 Mortality from tuberculosis in developed countries Tb evidenced in 4,000 BC 1839, Shoenlein recognized “tubercle” as fundamental lesion, ergo “tuberculosis”. 1882, Koch discovers mycobacterium tuberculosis 1804 Laennec associates lesions, describes “phthsis”
  17. 19. 0.5 100 1000 1700 1750 1800 1850 1900 1950 2000 1 5 10 50 YEAR MORTALITY rate per 100,000 Mortality from tuberculosis in developed countries Tb evidenced in 4,000 BC 1917 Flu pandemic 1882, Koch discovers mycobacterium tuberculosis 1804 Laennec associates lesions, describes “phthsis” 1839, Shoenlein recognized “tubercle” as fundamental lesion, ergo “tuberculosis”.
  18. 20. 0.5 100 1000 1700 1750 1800 1850 1900 1950 2000 1 5 10 50 YEAR MORTALITY rate per 100,000 Mortality from tuberculosis in developed countries Tb evidenced in 4,000 BC 1882, Koch discovers mycobacterium tuberculosis 1946, Streptomycin used as antibiotic 1917 Flu pandemic 1804 Laennec associates lesions, describes “phthsis” 1839, Shoenlein recognized “tubercle” as fundamental lesion, ergo “tuberculosis” .
  19. 21. Upstate New York
  20. 22. 18000 22000 26000 30000 1987 1981 1983 1985 YEAR REPORTED TB CASES US expected actual
  21. 23. 18000 22000 26000 30000 1987 1981 1983 1985 YEAR REPORTED TB CASES US HIV related expected actual
  22. 24. Natural history of tuberculosis in a newly infected (adult) contact (infection is not necessarily disease) CONTACT NO INFECTION INFECTION NO DISEASE DISEASE EARLY DISEASE LATE DISEASE Cell-mediated immunity Defenses (5%) (5%) (90%)
  23. 25. DIAGNOSIS: CMI CONTACT NO INFECTION NO DISEASE DISEASE EARLY DISEASE LATE DISEASE Defenses (5%) (5%) (90%) INFECTION cell-mediated immunity
  24. 26. DIAGNOSIS: CMI CONTACT NO INFECTION NO DISEASE DISEASE EARLY DISEASE LATE DISEASE Defenses (5%) (5%) (90%) INFECTION cell-mediated immunity PPD positive
  25. 27. The TB Skin Test: MATERIALS <ul><li>OLD TUBERCULIN </li></ul><ul><ul><li>culture of TB bacillus in glycol peptone broth </li></ul></ul><ul><ul><li>TB “tine” test </li></ul></ul><ul><li>PURIFIED PROTEIN DERIVATIVE (PPD) </li></ul><ul><ul><li>TB bacillus grown in Long’s media, filtered after heating </li></ul></ul><ul><ul><li>adopted by WHO as standard in 1950 </li></ul></ul><ul><ul><li>PPD-S 1952 </li></ul></ul><ul><ul><li>dose = 5 IU </li></ul></ul>
  26. 28. The TB (Mantoux) Skin Test <ul><li>Intra-dermal </li></ul><ul><ul><li>quality control important </li></ul></ul><ul><ul><li>trained practioner necessary </li></ul></ul><ul><li>Delayed hypersensitivity </li></ul><ul><ul><li>cell mediated </li></ul></ul><ul><ul><li>48-72 hours </li></ul></ul><ul><li>False negative </li></ul><ul><ul><li>immuno-compromized conditions </li></ul></ul><ul><ul><li>measles/measles immunizations </li></ul></ul><ul><li>Nonspecific reactions </li></ul><ul><ul><li>increase >10 IU </li></ul></ul><ul><ul><li>cross reactions, atypical MB </li></ul></ul>
  27. 29. Factors causing decreased ability to respond to tuberculin <ul><li>Factors related to the person being tested </li></ul><ul><ul><li>Infections </li></ul></ul><ul><ul><ul><li>Viral (measles, mumps, chickenpox) </li></ul></ul></ul><ul><ul><ul><li>Bacterial (typhoid fever, brucelosis, typhus, pertussis, overwhelming TB, </li></ul></ul></ul><ul><ul><ul><li>Fungal (South American blastomycosis) </li></ul></ul></ul><ul><ul><li>Live virus vaccinations (MMR) </li></ul></ul><ul><ul><li>Metabolic derangements (chronic renal failure) </li></ul></ul><ul><ul><li>Nutritional factors (severe protein depletion) </li></ul></ul><ul><ul><li>Diseases affecting lymphid organs (Hodgkin’s lymphoma, chronic lymphocytic leukemia, sarcoidosis) </li></ul></ul><ul><ul><li>Drugs (corticosteroids, other immunosuppressive agents) </li></ul></ul><ul><ul><li>Age (newborn, elderly) </li></ul></ul><ul><ul><li>Recent overwhelming infection with M. tuberculosis </li></ul></ul><ul><ul><li>Stress (surgery, burns, mental illness, graft versus host reactions) </li></ul></ul><ul><li>Factors related to the tuberculin used </li></ul><ul><li>Factors related to the method of administration </li></ul><ul><li>Factors related to reading the test and recording results </li></ul>
  28. 30. Indications for skin test screening <ul><li>Persons with signs and/or symptoms suggestive of tuberculosis disease </li></ul><ul><li>Recent contacts of persons known or suspected to have tuberculosis </li></ul><ul><li>Persons with undiagnosed upper lobe fibrotic lesions </li></ul><ul><li>Persons infected with HIV </li></ul><ul><li>Alcoholics and intravenous drug abusers </li></ul><ul><li>Persons with medical conditions known to increase the risk of disesase if infection has occurred: </li></ul><ul><ul><li>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 </li></ul></ul><ul><li>Groups at high risk of infection: </li></ul><ul><ul><li>Latin America, Oceana, medically underserved populations, residents of long term care facilities </li></ul></ul><ul><li>Groups that would pose a significant risk to others if diseased: employees of health care facilities, schools, child care facilities </li></ul><ul><li>ATS/CDC </li></ul>
  29. 31. TB PATHOPHYSIOLOGY <ul><li>systemic infection </li></ul><ul><li>primary infection/disease </li></ul><ul><li>progressive primary disease </li></ul><ul><li>miliary disease </li></ul><ul><li>meningitis </li></ul><ul><li>chronic TB (re-activation) </li></ul>
  30. 32. Inhalation of Infected Droplet Nuclei non-specific bronchopneumonia complete resolution (rare) progression healing with granuloma formation stable breakdown with development of (re-activation)TB DISEASE 1) skin test sensitization 2) resistance to exogenous reinfection 3) lympho-hematogenous spread massive necrosis (rare)
  31. 33. TB: PRIMARY Infection <ul><li>95% of cases begin with pulmonary focus </li></ul><ul><li>usually a SINGLE focus </li></ul><ul><li>hypersensitivity develops 2 to 6 weeks </li></ul><ul><ul><li>until then, focus may grow larger </li></ul></ul><ul><ul><li>hypersensitivity brings caseation </li></ul></ul>
  32. 34. Jha, A. K. et al. N Engl J Med 2004;350:2399-2404 Tissue Specimens Obtained at Autopsy from the Patient
  33. 35. PRIMARY Infection: Lympho-hematogenous spread <ul><li>8-14 weeks after onset of TB </li></ul><ul><li>usually occult </li></ul><ul><li>Mantoux positive during this phase </li></ul><ul><li>body wide seeding occurs during this phase </li></ul><ul><ul><li>bone, kidney, meninges etc. </li></ul></ul><ul><ul><li>3% of children with nl CXR’s develop calcifications in lung apices (SIMON FOCI) </li></ul></ul>
  34. 36. Jha, A. K. et al. N Engl J Med 2004;350:2399-2404
  35. 38. PRIMARY TB: endo-bronchial consequences <ul><li>lymph nodes draining primary infection site become involved </li></ul><ul><li>lymph node capsule becomes adherent to bronchial wall </li></ul><ul><ul><li>infection can progress to ulceration into the bronchial wall </li></ul></ul><ul><ul><li>bronchial compression occurs with more than one node at same level </li></ul></ul><ul><ul><li>with healing, bronchial constriction/stenosis can occur </li></ul></ul>
  36. 39. INFECTION TO ENDO-BRONCHIAL DISEASE TO STENOSIS
  37. 40. HEALED PRIMARY INFECTION SIMON FOCI CALCIFIED nodes and peripheral lesion (Ghon complex) other VISCERAL sites
  38. 41. USUAL PROGRESSION OF PRIMARY INFECTION infection lympho-hematogenous spread healed PRIMARY infection
  39. 42. PROGRESSIVE PRIMARY TB ( DISEASE) <ul><li>occasional (3.7%) local progression, despite hypersensitivity (more common in younger pt) </li></ul><ul><li>can be cavitary </li></ul><ul><li>can have endo-bronchial spread </li></ul><ul><li>similar in appearance to adult type, “reactivation” disease </li></ul><ul><li>2/3 of cases progress to death in the untreated </li></ul>
  40. 43. PROGRESSIVE PRIMARY DISEASE pleural effusion cavitation lymph node involvement
  41. 44. Progressive Primary Disease
  42. 45. ENDOBRONCHIAL SPREAD WITH SUBSEQUENT BRONCHOPNEUMONIA
  43. 46. Disseminated TB pneumonia
  44. 47. MILIARY Disease Generalized Hematogenous Tuberculosis <ul><li>generalized dissemination through bloodstream </li></ul><ul><ul><li>caseous focus ruptures into blood vessel </li></ul></ul><ul><ul><li>growth of tubercle within the blood vessel </li></ul></ul><ul><ul><li>may be acute, occult or chronic </li></ul></ul><ul><li>uniformly fatal if not treated </li></ul><ul><li>rare </li></ul><ul><li>usually occurs in the first 4 months after primary infection </li></ul>
  45. 48. <ul><li>millet seed appearance on X-ray </li></ul><ul><li>Mantoux positive? </li></ul><ul><li>Most children still have active primary complex when miliary disease strikes </li></ul><ul><li>most develop meningitis </li></ul>MILIARY Disease
  46. 49. Major sites of extra-pulmonary tuberculosis among children in the United States <ul><li>SITES % Avg. Age </li></ul><ul><li>lymphatics 67 5y </li></ul><ul><li>meninges 13 3y </li></ul><ul><li>pleura 6 16y </li></ul><ul><li>miliary 5 1y </li></ul><ul><li>skeletal 4 5y </li></ul><ul><li>other 5 </li></ul><ul><li>Clin Chest Med 1989, Am. Rev. Resp. Dis, 1990 </li></ul>
  47. 50. TB MENINGITIS <ul><li>primary seeding </li></ul><ul><li>caseous lesion adjacent meninges </li></ul><ul><li>growth/discharge </li></ul><ul><li>usually insidious </li></ul><ul><li>prophylaxis is preventive </li></ul>
  48. 51. TB MENINGITIS <ul><li>40% of cases ocur within 3 months of estimated onset of TB </li></ul><ul><ul><li>rarely < 1 month </li></ul></ul><ul><li>90% with TB menningitis PPD positive </li></ul><ul><ul><li>94% of these have positive CXR’s </li></ul></ul><ul><li>average duration from meningitis diagnosis to death (untreated) 19.5 days </li></ul>
  49. 52. CHRONIC PULMONARY TB (re-activation/adult type) <ul><li>occurs only after primary infection </li></ul><ul><ul><li>0.5-10 % incidence (7% by Lincoln) </li></ul></ul><ul><ul><li>usually not less than 1 year of age </li></ul></ul><ul><ul><li>most cases occur when primary infection aquired after 7 years of age </li></ul></ul><ul><li>minute areas of bronchopneumonia </li></ul><ul><li>tissue hypersensitivity - cavity formation </li></ul><ul><li>few symptoms early on in disease </li></ul>
  50. 53. Annual risk of developing chronic pulmonary tuberculosis among survivors of pulmonary primary tuberculosis ( Dis Chest 38:473, 1960 ) Rate per 1000 Age in years 0 2 4 6 8 10 12 0 2 4 6 8 10 12 14 16 18 20
  51. 55. Major sites of extrapulmonary tuberculosis among children in the United States <ul><li>SITES % Avg. Age </li></ul><ul><li>lymphatics 67 5y </li></ul><ul><li>meninges 13 3y </li></ul><ul><li>pleura 6 16y </li></ul><ul><li>miliary 5 1y </li></ul><ul><li>skeletal 4 5y </li></ul><ul><li>other 5 </li></ul><ul><li>Clin Chest Med 1989, Am. Rev. Resp. Dis, 1990 </li></ul>
  52. 57. DEATHS from TB in children (natural course of the disease) <ul><li>higher incidence in younger children </li></ul><ul><li>25% of children will die in the untreated state </li></ul><ul><li>90% of the deaths will occur in the first year </li></ul>
  53. 58. INH PROPHYLAXIS <ul><li>the best prophylaxis is AVOIDING exposure </li></ul><ul><li>for patients with quiescent, uncomplicated, non-active disease </li></ul><ul><li>reduces antigen load, thereby decreasing risk of (re)activation </li></ul>
  54. 59. PULMONARY TUBERCULOSIS LOOK ALIKE...
  55. 60. TB like manifestations
  56. 62. TB IN CHILDREN SUMMARY <ul><li>There is no such thing as a positive PPD from just “being exposed” to the disease </li></ul><ul><li>primary vs reactivation disease </li></ul><ul><li>children with primary TB are rarely “communicable” </li></ul><ul><li>untreated, there is high morbidity and mortality </li></ul><ul><li>children with quiescent disease deserve prophylaxis </li></ul><ul><li>prophylaxis is “essentially” curative </li></ul>

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