1. Tuberculosis in children Zhi-min Chen Dept. Pediatric Pulmonology ， Children’s Hospital Email: zmchen@zju.edu.cn Pediatrics

2. Tubercle bacillus Oder Actinomycetales Family mycobacteriaceae Genus Mycobacterium(M.) Species M. tuberculosis M. bovis Non-TB M.

3. Chronicle of Tuberculosis  1882 Discovery of TB(Robert Koch)  1921 BCG development  1944 Invention of streptomycin  1952 Invention of Isoniazid  1966 Invention of Rifampin  ………

4. Characteristics  Acid-fastness  ziehi-Neelsen  Slow-growing  Unusual resistance  Multi-Drug Resistance strain(MDR)

5. Source of infection Open Pulmonary Tuberculosis (adult)  acid-fast smear of sputum(+)  copious production of thin sputum  severe and forceful cough  extensive upper lobe infiltrate or cavity Young children with TB rarely infect others

6. Route of transmission  By respiratory tract: airbone mucus droplet nuclei contaminated dust  By alimentary tract raw milk contaminated food  By others: (Placenta,skin) Transmission rarely occurs by direct contact with an infected discharge or contaminated fomite!

7. High-risk population  Genetic background: twin racial difference HLA BW35  Environmental factors: socioeconomic status overcrowding poor nutrition inadequate health care

8. TB infection and TB disease  TB infection:  inhalation of infective droplet nuclei containing TB  A reactive tuberculin skin test and the absence of clinical and radiographic manifestations  TB disease:  Signs and symptoms, or radiographic changes become apparent

9. From TB infection to TB disease Light J,et al. Curr Probl Pediatr adolesc Health Care,2009; 39:61

10. Infection, disease or not  Virulence of the TB strain  The size of inoculin  The hypersensitivity of the individual tissues  Nutritional or social status  Immunologic status  Genetic background

11. Primary Pulmonary Tuberculosis Pediatrics

12. Spreading of M.tuberculosis Initial focus (local infection at the portal of entry) Draining lymphatic vessles Regional lymph nodes Blood Other tissues of the body

13. Primary pulmonary tuberculosis Clinical types Initial focus  Primary complex lymphangitis Lymphadenitis  Bronchial lymph node tuberculosis

14. Primary pulmonary tuberculosis Clinical manifestation  Surprisingly meager(subclinical)  Infants more likely to develop signs and symptoms  Nonproductive cough and mild dyspnea as the most common symptoms

15. Primary pulmonary tuberculosis Less common symptoms  Systemic complaints fever, night sweats, failure-to-thrive, anorexia, etc.  Bronchial irritation or obstruction localized wheezing

16. Prognosis  Improve or dissolve  Completely resolution  Induration  Calcification  Local progress  Exacerbation

17. Tuberculous meningitis  Most common in children of 6mo~4yr  Usually develops during the lymphohematogenous dissemination of the primary infection  High mortality and high morbidity

18. Tuberculous meningitis: Clinical manifestation  Stage 1: Prodromal stage  Stage 2: Transitional stage  Stage 3: Terminal stage

19. Stage 1: Prodromal stage  Lasts 1~2wk  Nonspecific symptoms: character alteration, fever, headache, malaise, irritability, drowsiness  Focal neurologic signs absent

20. Stage 2: Transitional stage  Increased intracranial pressure: headache, projectile vomiting, papilledema  Meningeal irritation: nuchal rigidity, Kernig’s sign, Brudzinski’s sign  Toxic appearance: fever, anorexia, nausea  Others: cranial nerve palsies, convulsion

21. Stage 3: Terminal stage  1~3wk  Exacerbation of neurologic symptoms  Very thin with scaphoid abdomen  Electrolyte imbalance SIADH Cerebral salt losing syndrome

22. Diagnosis  Laboratory study  Clinical diagnosis

23. Typical CSF picture of tuberculous meningitis, but NOT specific  Pressure  Appearance ground-glass  Cell counts 50~500×106/L, L. predominates  Protein  Glucose <40mg/dl ， or CSF/blood <50%  Chloride

24. Diagnosis  Laboratory study  isolation of M. tuberculosis: most specific Smear acid-fast staining Culture (BACTEC, liquid, coloricmetric) PCR and Gene probe

25. Diagnosis  Laboratory study  Isolation of M. tuberculosis  Serology: limited value LAM antibody 38kDa antibody 16kDa antibody …

26. Diagnosis  Laboratory study  Isolation of M. tuberculosis  Serology  biopsy and histology : pathognomonic Caseous necrosis and encapsulation

27. Diagnosis  Laboratory study  Others INF-γ Releasing Assays( IGRAs): promising –INF-γ produced by T-cell responses to M.tb-special antigens called early secreted antigenic target 6 (ESAT-6) and culture filtrate protein10. –Commercial kits: Quantiferon-TB Gold In- tube (QFT) and The T-Spot TB (T-Spot) test

28. Diagnosis  Laboratory Study  Clinical diagnosis  History  Clinical manifestation  Tuberculin test  Roentgenographic examination  Therapeutic trial

29. Diagnosis  Laboratory Study  Clinical diagnosis  History: usually need chest film or CT of her parents or family members  Clinical manifestation  Tuberculin test  Roentgenographic examination  Therapeutic trial

30. Case report  6-month-old girl  Born in San Francisco, but her parents immigrated to USA from China 8 yrs ago.  Chief Complaint  cough and fever for 3 weeks and tachypnea for 1 week.  No response to routine antibiotic therapy

31. Diagnosis  Laboratory Study  Clinical diagnosis  History  Clinical manifestation: Not specific  Tuberculin test  Roentgenographic examination  Therapeutic trial

32. Diagnosis  Laboratory Study  Clinical diagnosis  History  Clinical manifestation  Tuberculin test: more valuable  Roentgenographic examination  Therapeutic trial

33. Tuberculin test ： principle & method  Based on delayed type hypersensitivity( type IV)  Two antigen preparations: Old tuberculin, OT Protein purified derivative, PPD  Intradermal injection of 0.1ml containing 5 tuberculin units of PPD (Mantoux test)

34. Tuberculin skin test: result evaluation  The amount of induration should be measured by a trained person 48~72hours after administration  Intensity: – or ±: <5mm negative or doubtful + : 5~9mm suspicious ++ : 10~19mm positive +++ : >=20mm strong-positive ++++ : blister,ulcer,lymphangitis,double rings

35. Interpretation of PPD test

36. What does it mean: Positive result  Previous infection with TB  Previous vaccination with BCG  Active tuberculosis  <=3 year without prior vaccination  > = 15mm  conversion occurring within 2 years

37. What does it mean: Negative result  Not infected with TB  False-negative : incubation period immunosuppression or immunodeficiency technical error or improper reagents

38. Diagnosis  Laboratory Study  Clinical diagnosis  History  Clinical manifestation  Tuberculin test  Roentgenographic examination: helpful  Therapeutic trial

39. Diagnosis  Laboratory Study  Clinical diagnosis  History  Clinical manifestation  Tuberculin test  Roentgenographic examination  Therapeutic trial: final

40. Prevention of TB  Avoiding contact with those with open pulmonary tuberculosis  BCG (Bacillus Calmette-Guerin) vaccination  Chemoprophylaxis

41. Prevention of TB  Avoiding contact with those with open pulmonary tuberculosis  BCG (Bacillus Calmette-Guerin) vaccination  Chemoprophylaxis Tuberculosis control programs involve case finding and treatment.

42. Treatment  Antituberculosis therapy:  early, dosage, combination, regular, whole course  intensification stage and consolidate stage  directly observing therapy shortcourse (DOTS)  Corticosteroids  Symptomatic management  Supportive care

43. Recommended treatment regime

44. Pediatrics Pertussis and Pertussis syndrome

45. Definition  Pertussis (whooping cough)  caused by Bordetella pertussis,  The pertussis syndrome  includes disease caused by Bordetella pertussis and certain other infectious agents

46. Etiology  Bordetella pertussis  tiny, Gram-negative, coccobacilli  Other infectious agents  Bordetella parapertussis  Adenovirus  Dual infection (of above)  Other common pathogens of protracted cough: mycoplasma, chlamydia, RSV, parainfluenza virus

47. Epidemiology  Infect only humans and transmitted person to person by coughing  Most contagious during the earliest stage  The peak incidence <4 m  The annual rate--100 to 200/100,000, higher in developing countries

48. Clinical manifestation  The mean incubation period is 6 days.  The progression of pertussis  Catarrhal stage  Paroxysmal stage  Convalescent stage

49. Clinical manifestation  Catarrhal stage  nonspecific signs Injection increased nasal secretions low-grade fever  last 1 to 2 weeks

50. Clinical manifestation  The paroxysmal stage  approximately 2 to 4 weeks.  as catarrhal symptoms wane, coughing begins first as a dry, intermittent, irritative hack;  then evolve into coughing in paroxysms during expiration, causing young children to lose their breath (machine-gun burst of uninterrupted coughs).

51. Clinical manifestation  The paroxysmal stage  After the most insignificant startle from a draught, light, sound, sucking or stretching, a well- appearing young infant begins to choke, gasp, and flail extremities, eyes watering and bulging, face reddened or purple, tongue protruding maximally until at the seeming last moment of consciousness.  Characteristic whoop follows this paroxysm of cough (the forceful inhalation against a narrowed glottis).  Others: post-tussive emesis, conjunctival hemorrages and petechiae on the upper body

52. Clinical manifestation  The Convalescent stage  gradual resolution of symptoms over 1 to 2 weeks.  residual cough may persist for months, especially with physical stress or respiratory irritants

53. Clinical manifestation  Young infants may not display the classic pertussis syndrome:  the first signs may be episodes of apnea  unlikely to have the classic whoop  more likely to have CNS damage as a result of hypoxia  more likely to have secondary bacterial pneumonia.

54. Laboratory studies  The diagnosis depends on isolation of B. pertussis  Culture of nasopharyngeal swabs  Direct fluorescent antibody staining  Serologic tests are not useful for diagnosis of acute infection.  Leucocytosis (20,000~ 50,000/mm 3 ) with lymphocytosis is characteristic beyond the neonatal age

55. Imaging study  NOT specific  Segmental lung atelectasis  not unusual during pertussis, especially during the paroxysmal stage.  Perihilar infiltrates  common and similar to what is seen in viral pneumonia.

56. Diagnosis and differential diagnosis  the diagnosis based on recognition of the pattern of illness is quite accurate  Respiratory viruses such as RSV, parainfluenza virus, and C. pneumoniae among infants and M. pneumoniae in older children may produce a bronchitic illness that is not distinguished easily from pertussis.

57. Complications  Major complications:hypoxia, apnea, pneumonia, seizures, encephalopathy, and malnutrition.  The most frequent complication is pneumonia caused by B. pertussis itself or resulting from secondary bacterial infection from S. pneumoniae, Hib, and S. aureus.

58. Complications  Other complications  atelectasis, pneumomediastinum, pneumothorax, or interstitial or subcutaneous emphysema; epistaxis; hernias; and retinal and subconjunctival hemorrhages, otitis media and sinusitis.

59. Goal of therapy  Limit the number of paroxysms  Observe the severity of cough to provide assistance when necessary  Maximize nutrition, rest, and recovery without sequelae

60. Treatment  Erythromycin  given early, eradicates nasopharyngeal carriage of organisms within 3 to 4 days and ameliorates the effects of the infection.  not effective in the paroxysmal stage.  Azithromycin and clarithromycin  TMP-SMZ  Pertussis-specific immunoglobulin ( effective)

61. Prevention  Active immunization  acellular pertussis vaccine, given in combination with the toxoids of tetanus and diphtheria (DTaP with an efficacy of 70% to 90%;  Compared with older, whole cell pertussis vaccines, acellular vaccines have fewer adverse effects and local reactions.

62. Prevention  Erythromycin and other macrolides  effective in preventing disease in contacts exposed to pertussis.

63. Prevention  Close contact <7y  should be given a macrolide antibiotic.  should receive a booster dose of DTaP, unless a booster dose has been given within the preceding 3 years.  Close contact > 7y  prophylactic macrolide antibiotic for 10 to 14 days  NOT the vaccine.

64. Q&A OR E-mail to zmchen@zju.edu.cn

65. Thank you for your attention