- Tuberculosis is caused by the bacterium Mycobacterium tuberculosis and mainly affects the lungs, but can spread to other organs. It is transmitted through airborne droplets when infected people cough, sneeze or speak. - China has the second largest tuberculosis epidemic in the world after India, with over 1.3 million new cases reported each year. Risk factors include poverty, malnutrition, HIV infection, and living/working conditions like overcrowding. - Tuberculosis infection can either remain latent or progress to active disease. Diagnosis involves tuberculin skin tests, chest x-rays, sputum smears, and culture tests. Standard treatment uses a combination of antibiotics like isoniazid and

1. Childhood Tuberculosis 檀卫平 中山二院 Tan-weiping

2. Definition Tuberculosis is caused by Mycobacterium tuberculosis , isolated by Robert Koch in 1882 , M.bovis(seldom) mainly involves the lungs, but may spread to other organs consumption （肺痨）

3. Epidemiology 19th century, 25% deaths by TB 1940s, effective medicines Annually, 8 million become ill with tuberculosis, 2 million people die China has the world's second largest tuberculosis epidemic (after India ), 1.3 million new cases every year Work migrants "floating" peasants migrant population:100 million incidences rates 113 per 100,000 in China

4. Epidemiology The morbidity / mortality of tuberculosis are high in developing countries (southeast asia,China,India,Africa,latin america) Age:60% Infant - <5yr Favored age:5-14yr Male:female-1:1(adults male predominate)

5. Epidemiology TB adults exposure Immunocompromise malnutrition HIV/AIDS infection Poverty,immigration irregular treatment breeds : drug-resistant tuberculosis

6. Risk factors Socioeconomic status Over-crowding Poor nutrition Inadequate health care HIV infection Drug abuse

7. Etiology Tubercle bacillus: aerobic, grows slowly non-Motile,non-spore-forming, highlipid content acid-fast , weak Gram(+) Sensitive to heat/sunlight tolerate in humid or dry or cold. withstand weak disinfectants and survive in a dry state for weeks .

8. Dr. Robert Koch discovered the tuberculosis bacilli in 1882 He received the Nobel Prize in physiology or medicine in 1905 for this discovery

9. Tuberculosis is transmitted by airborne droplet nuclei(containing tubercle bacilli ) prolonged, frequent, or intense contact cough, sneeze, speak, or spit

10. Many droplet nuclei are capable of floating in environment for several hours Large particles may be inhaled by person breathing the same air and impact on the trachea or wall of the upper airway

11. The transmission is determined The probability of contact with active — not latent — TB intimacy and duration of contact effectiveness of ventilation number s and virulence of the M. tuberculosis strain in infectious droplets

12. Pathogenesis tubercle bacillus Human immunity

13. Pathogenesis 90% infected with Mycobacterium tuberculosis asymptomatic, latent TB infection 10% progress to TB disease if untreated, the death rate for these active TB cases is more than 50%

14. Pathogenesis mycobacteria -> pulmonary alveoli -> replicate within macrophages -> picked up by dendritic cells -> transport to local LN -> spread through bloodstream to other tissues/organs -> secondary TB lesions primary site of infection : upper part of the lower lobe, or lower part of the upper lobe of lung secondary TB lesions: apex of the upper lobes , peripheral lymph nodes, kidneys, brain, and bone

15. Human Immunity /hypersensitivity after TB infection Specific immunity after infected or given BCG vaccine Cell-mediate immunity develops within 4-8 weeks after infected with bacillus Many immunologic cells: Macrophages, T/B lymphocytes, fibroblasts involved

16. Two types of cells are essential in the formation of TB Macrophages: directly phagocytize TB and processing and presenting antigens to T lymphocyte T lymphocytes(CD4+): induce protection through the production of lymphokines

17. T lymphocytes(CD4+) Many lymphokines are involved in tuberculosis, the interplay of these cytokines determine the hosts response for example IL-1 is related to fever IL-6 is related to hyperglobulinemia TNF is related to the killing of mycobacteria formation of granulomas other cytokines including IL-4,IL-5,IL-10 can promote humoral immunity

18. Genetic factors ( HLA-BW35) play a key role in innate non-immune resistance to infection with M. Tuberculosis These genes may have a role in determining susceptibility to tuberculosis

19. Basic pathologic changes infiltration -> hyperplasia( granuloma) , ulceration or calcification in different stage host defense < bacterias, caseating ulceration( caseous necrosis ) -> fibrosis host defense > bacteria, granuloma calcification

20. A characteristic tubercle at low magnification ( A ) and in detail ( B ) central caseation surrounded by epithelioid and multinucleated giant cells(C) mycobacteria with acid-fast stains ( D ).

21. Progression of tuberculosis Absorption Fibrosis Calcification Deterioration: enlargement of infected aeras and appear newer infiltrated regions or spreading.

22. Five common clinical patterns 1. Primary pulmonary tuberculosis (Primary Complex and Bronchial Lymphnode-Tuberculosis) 2. Milliary Tuberculosis (acute, subacute and chronic hematogenous pulmonary tuberculosis) 3. secondary pulmonary tuberculosis Infiltrative pulmonary tuberculosis Chronic fibrocavenous pulmonary tuberculosis 4.Tuberculous pleuritis 5.Extrapulmonary tuberculosis

23. Diagnosis History and Clinical Manifestations Tuberculin testing Lab examination X-r ay bronchoscopy Puncture of adenopathy

24. History /Clinical Manifestations systemic signs : fever, weight loss, fatigue, night sweats, wasting,coughing up blood, Chest pain. TB Contaction ： adults in family History of BCG Vaccination Acute infectious disease recently : measles,whooping cough Allergy to TB ： erythema nodosum 、 herpetic conjunctivitis

25. Tuberculin skin test a skin test to determine past or present infection with the tuberculosis bacterium; based on hypersensitivity of the skin to tuberculin Method of test protein purified derivative PPD 0.1ml intradermal injection Site : internal side of medium-distal 1/3 left forearm 6 - 10mm Result : 48-72hrs, transverse diameter

26. Result is read by measuring the diameter of induration 48-72hrs Induration <5mm negative Induration 5-9mm(+) Induration 10-19mm(++) Induration 》 20mm (+++) A positive tuberculin skin test indicates tuberculous infection, with or without disease

27. Tuberculin testing A positive tuberculin test is of great use in children, with limited diagnostic significance in adults

28. Clinical Significance Positive Negative

29. Positive Reaction : indicates TB exposure BCG Vaccination Children and adolescents(++) exposed to TB Infant﹤3yrs (++) recent infection (+++) Active TB infectin (-) -> (+) ， or Induration<10mm ->>10mm, ↑>6mm recent infection

30. Negative Reaction Never exposed to TB Within 4-8wks of primary infectin False negative:compromised immunity Technique failure or PPD invalidated

31. PPD reaction of natural TB infection and BCG vaccination Natural infection stronge Induration >10-15mm deep red 、 regular margin 、 hard pigmentation Long duration > 7-10d Less change BCG vaccination weak Induration 5-9mm light red 、 unregular margin 、 soft Short duration:2-3d Become weak gradually,disappear3-5y

32. Laboratory examinations Sputum examination acid-fast staining ----LED microscopes DNA-based diagnosis :PCR test TB antibody testing ESR Blood Routine

33. Isolation of M. tuberculosis automatic radiometric methods: such as BACTEC—1-3wks

34. Chest radiography Chest X-ray: most important method to detect TB Characteristics ,area, degree of activity or progress Differentiation with other disease Follow the effectivity of therapy

35. bronchoscopy Endobrochial tuberculosis tuberculous tracheobronchial lymphadenitis

36. Puncture of peripherial LN Tubercle caseous necrosis

37. Table 39-1 -- The Stages of Tuberculosis in Children The Stages of Tuberculosis in Children Three or four One One Number of drugs Always Always If <5 years old Treatment Usually abnormal Usually normal Normal Chest radiograph Usually abnormal Normal Normal Physical examination Positive (90%) Positive Negative Skin test Disease Infection Exposure STAGE

38. Treatment Common therapy : Nutrition 、 Rest Ventilation Isolation

39. Chemotherapy goal : Kill TB Limit TB from spreading principles : earlier, appropriate Combination, Full course regularly and Staged .

40. Classification of antitubercular drug bactericidal （ 1 ） complete bactericidal ： INH 、 RFP （ 2 ） semi- bactericidal ： SM ： alkaline, fast propagation, intracellular TB ( Pyrazinamide) PZA ： Acidic 、 slow growth intracellular TB

41. medicines are classified as first-line and second-line agents First-line essential antituberculous agents are the most effective and are necessary components of any short-course therapeutic regimen

42. First-line medicines include Isoniazid, rifampin, pyrazinamide,streptomycine Second-line medicines include ethambutal, para-amino-salicylic acid, kanamycin, amikacin and ects. Newer antituberculous drugs rifapentine, rifabutin quinolones

43. Isoniazid (INH) first-line drug Isoniazid is a principal agent used to treat TB It is universally accepted for initial treatment Now considered the best anti-TB drug It should be included in all TB treatment regimens unless the organism is resistant

44. Advantages Inexpensive Readily synthesized Availabe worldwide Highly selective for mycobacteria Well tolerated(about only 5% of patients exhibiting adverse effects )

45. Dosage Tuberculosis organization have recommended 5 mg/kg daily for both groups Generally, 300mg daily oral dose is adopted

46. Adverse effects The two most important adverse effects of isoniazid therapy are hepatotoxicity peripheral neuropathy We must measure liver enzymes before administrating and during treatment periods(usually monthly measure) If the liver enzymes level is higher than normal,the drug must be discontinued

47. Rifampin (RFP) first-line drug It is also considered the most important and potent antituberculous agent Like isoniazid it is bactericidal and highly effective Unlike isoniazid, it is also effective against most other mycobacteria as well as other organisms

48. Chemotherapy Regimens Standard regimen ： asymptomatic primary infection INH 、 RFP and/ （ or ） EMB 9-12 months

49. Two Stage Therapy Active primary TB 、 Disseminated TB 、 TB meningitis Enforcement stage : 3-4 bactericidal ， 3-4m Consolidation stage : 2 drug ， 12-18m

50. Short-term Therapy DOTS (Directly Observed Treatment Short-course) 2 or 3 drugs killing of organisms + 1 drug restraint of organisms Mild/moderate with small infiltrates and thin wall cavities : INH+RFP+SM(EMB) (PZA) 2 M or INH+RFP 4 -7 M extensive /severe, large areas of caseation or thick-walled cavities are identified: INH+RFP+SM+EMB(PZA) 2 M or INH+RFP 4 -7 M

51. Prevention Prevention of Tuberculosis : Vaccination BCG Vaccination can obtain immunity acquired for tubercle bacillus. one of the most important tuberculosis prevention Vaccination target: infants children and youngster of tuberculin negative (vaccination is of course of no use in tuberculin-positive persons)

52. Prevention Finding patients earlier Treatment and management of patients Prevention with medicines The systemic organization of prevention

53. Prophylatic chemotherapy Intimate contact with family members suffering active TB <3y infant PPD test(++) without BCG viccination PPD test (-) -> (+) recently PPD test(++) accompanied by Tb toxic symptoms PPD test(++) ， suffered measles,whooping cough PPD test(++) and need long term steroid therapy

54. Regimen: INH ： 10mg/kg.d ， 6-9m

55. Tuberculous meningitis

56. Pathogenesis Spreading through bloodstream Rupture of TB lesion->bacteria enter choroids plexuses -> CSF Extension from nearby organ infected with TB

57. Clinical Manifestation The 1st Stage: 1-2wks change of character:irritability, Tb toxic symptom Headaches （ vomiting 、 drowsiness ）

58. The 2nd Stage 1-2wks Meningeal irritation stage Increased ICP: Headaches,vomiting, drowsiness, seizure, nuchal rigidity, back pain, Kerning sign, Brudzinski sign. Cranial Nerve palsy Encephalitis:disorentation,movement disorders, speech impaiment, papilledema

59. The 3rd Stage Coma stage 1-3wks coma, hemiplegia, paraplegia, convulsion consumption, abnormal metabolise of electrolyte hypertenion, decerebrate posture brain hernia->death

60. Diagnosis Medical history Clinical manifestation CSF examination Ｘ -ray check ＣＴ or ＭＲＩ scanning Tuberculin test

61. Differentiation diagnosis Meningococcal Meningitis Viral Meningitis cryptococcal meningitis Cerebral tumor

62. Treatment General therapy Anti-tuberculous therapy Decreasing intracranial pressure corticosteroids Anti-symptomatic therapy Follow -up

63. Anti-tuberculous therapy １、 The initial stage : ３－４ m ＩＮＨ、ＲＦＰ、ＰＺＡ、ＳＭ ２、 The 2nd stage ＩＮＨ、ＲＦＰ １２ m

64. Latent infection of tuberculosis A patient is infected with Mycobacterium tuberculosis , but does not have active disease Patients with latent tuberculosis are not infectious The main risk is that approximately 10% of these patients will go on to develop active tuberculosis at a later stage of their life The identification and treatment of people with latent TB is an important part of controlling this disease.

65. Miliary tuberculosis in an infant whose uncle also had tuberculosis. There is adenopathy in addition to the millet seed–like lesions

67. A posteroanterior (A) and lateral (B) chest radiograph of a child with hilar adenopathy caused by Mycobacterium tuberculosis.

68. Hilar and mediastinal adenopathy and a partial segmental lesion in a child with tuberculosis

69. Lobar pneumonia with bowing of the horizontal fissure in a child with tuberculosis. a secondary bacterial pneumonia may have been present

70. Tuberculous pleural effusion in a teenage girl. The pleural biopsy had caseating granulomas

72. A magnetic resonance image of tuberculoma in a child with culture-positive tuberculous meningitis. The child's presenting signs and symptoms included fever, altered mental status, and hemiparesis

73. Thank you